Cellular Migration and Formation of Neuronal Connections: Comprehensive Developmental Neuroscience
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The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms. Each volume in the series consists of review style articles that average 15-20pp and feature numerous illustrations and full references. Volume 2 offers 56 high level articles devoted mainly to Formation of Axons and Dendrites, Migration, Synaptogenesis, Developmental Sequences in the Maturation of Intrinsic and Synapse Driven Patterns.
- Series offers 144 articles for 2904 full color pages addressing ways in which the nervous system and its components develop
- Features leading experts in various subfields as Section Editors and article Authors
- All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship
- Volume 2 sections include coverage of mechanisms which regulate: the formation of axons and dendrites, cell migration, synapse formation and maintenance during development, and neural activity, from cell-intrinsic maturation to early correlated patterns of activity
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Cellular Migration and Formation of Neuronal Connections - Academic Press
Comprehensive Developmental Neuroscience: Cellular Migration and Formation of Neuronal Connections
Editors-in-Chief
Professor John L.R. Rubenstein
Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA
Professor Pasko Rakic
Duberg Professor of Neurobiology and Neurology, Director Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA
Table of Contents
Cover image
Title page
Copyright
Editors-in-Chief
Section Editors
Contributors
Introduction to Comprehensive Developmental Neuroscience
I: Formation of Axons and Dendrites
Chapter 1. Development of Neuronal Polarity In Vivo
1.1 Introduction
1.2 Axon Initiation In Vitro Versus In Vivo
1.3 Distinction Between Cues Regulating Axon Specification Versus Axon Growth
1.4 Extracellular Cues Regulating Neuronal Polarization and Axon Initiation
1.5 Intracellular Pathways Underlying Neuronal Polarization
References
Chapter 2. Role of the Cytoskeleton and Membrane Trafficking in Axon–Dendrite Morphogenesis
2.1 Introduction
2.2 Developmental Stages
2.3 Role of Cytoskeleton in Establishment of Neuronal Polarity
2.4 The Role of (Membrane) Trafficking During Neuronal Polarization
2.5 Maintaining Neuronal Polarity
2.6 Future Work on Neuronal Morphogenesis
References
Chapter 3. Axon Growth and Branching
3.1 Introduction
3.2 Cell Biological Mechanisms
3.3 Extracellular Regulation During Development
3.4 Intracellular Signaling Mechanisms
3.5 Concluding Remarks
References
Chapter 4. Axon Guidance: Semaphorin/Neuropilin/Plexin Signaling
4.1 Introduction: General Features of Axon Guidance
4.2 Discovery of the Semaphorin, Neuropilin, and Plexin Families
4.3 The Class 3 Secreted Semaphorins in Vertebrates: Neuropilin/Plexin Receptors and Signal Transduction Cascades
4.4 Generating Diversity of Axon Responses to Sema3’s
4.5 Uncovering the in vivo Contribution of Sema3’s to Axon Guidance: Insights from Animal Models
4.6 Sema3 Signaling and Sensorimotor Projections
4.7 Sema3 Signaling and Connections of the Cerebral Cortex
References
Chapter 5. Roles of Eph–Ephrin Signaling in Axon Guidance
5.1 Introduction
5.2 Eph–Ephrin Signaling Is Essential for Axon Guidance in Many Contexts
5.3 Modes of Eph–Ephrin Signaling in Axon Guidance
5.4 Eph–Ephrin Signaling in Invertebrate Nervous Systems
5.5 Eph Signaling in Axon Regeneration
Acknowledgments
References
Chapter 6. Axon Guidance: Slit–Robo Signaling
6.1 Introduction
6.2 Slits and Their Receptors
6.3 Slit–Robo Function in Midline Crossing
6.4 Modulation of Slit–Robo Signaling
6.5 Signaling Downstream of Robo
6.6 Beyond the Midline: Additional Roles for Slit–Robo in the Nervous System
6.7 Slit–Robo Contributions to Axon Targeting in a Complex Target Field
6.8 Involvement of Slit–Robo in Disorders of the Nervous System
6.9 Slit–Robo: Players Outside the Nervous System
6.10 Conclusion
References
Chapter 7. Nonconventional Axon Guidance Cues
7.1 Introduction
7.2 Morphogens
7.3 Morphogens in Axon Guidance
7.4 Conclusion and Perspectives
Acknowledgments
Glossary
References
Chapter 8. Axon Regeneration
8.1 Introduction
8.2 Inhibitors of CNS Axon Regeneration
8.3 The Physiological Function of CNS Regeneration Inhibitors and Their Receptors
8.4 Therapeutic Implications and Future Directions
8.5 Conclusions
See also
Acknowledgments
References
Chapter 9. Axon Maintenance and Degeneration
9.1 Introduction
9.2 Essential of Axonal Transport in Axon Maintenance
9.3 Proteasome and Autophagy Pathways in Axon Homeostasis
9.4 Role of Glial Cells in Axon Maintenance
9.5 Maintaining Axon Track Positions
9.6 Axon Pruning and Axon Degeneration
References
Chapter 10. Dendrite Development: Invertebrates
10.1 Structure and Anatomy of Invertebrate Dendrites
10.2 Methods for Manipulating and Studying Dendrite Morphology in Drosophila
10.3 Anatomical Background for Key Model Systems in Which Dendritic Morphogenesis Is Studied in Invertebrates
10.4 Cell Biology of Dendritic Growth
10.5 Transcriptional Control of Dendritic Morphology
10.6 Posttranscriptional Control of Dendritic Development
10.7 Control of Dendritic Field Formation I: Guidance and Targeting
10.8 Control of Dendritic Field Formation II: Dendritic Self-Avoidance and Tiling
10.9 Dendritic Remodeling
See also
References
Chapter 11. Dendritic Development: Vertebrates
11.1 Introduction
11.2 Molecular and Cellular Control of Dendrite Development
11.3 Regulation of Growth Direction
11.4 Regulation of Extension and Branching
11.5 Local Adaptation and Rapid Turnover of Dendrites to Meet Synaptic Partners
11.6 Emergence of Dendritic Geometry and Structural Specializations for Integration and Computation
11.7 Dendrite Development and Neurodevelopmental Disorders
11.8 Conclusion
Acknowledgments
References
II: Migration
Chapter 12. Cell Polarity and Initiation of Migration
Abbreviations
12.1 Introduction
12.2 Migratory Behaviors During Radial Migration in the Developing Cerebral Cortex
12.3 Molecular Mechanisms That Regulate the Initiation of Migration and Cell Polarity During Migration
12.4 Conclusion
See also
Glossary
References
Chapter 13. Leading Process Dynamics During Neuronal Migration
13.1 Introduction
13.2 Diverse Leading Process Dynamics During Neuronal Migration
13.3 Cytoskeleton Dynamics in Migrating Neurons
13.4 General Perspective
Acknowledgments
References
Chapter 14. Nucleokinesis
14.1 Nucleokinesis: Overview
14.2 The Nucleus
14.3 Interactions Between the Nucleus and the Cytoskeleton
14.4 The Cytoskeleton
14.5 Cell Polarity
14.6 Conclusions and Future Directions
Acknowledgments
References
Chapter 15. Migration in the Cerebellum
15.1 Migration of Cerebellar Neurons in the Developing Cerebellum
15.2 Regulation of Granule Cell Migration by Calcium Signaling and Neuropeptides
15.3 Alcohol Impairs Granule Cell Migration
References
Chapter 16. Radial Migration in the Developing Cerebral Cortex
16.1 Introduction
16.2 Production of Cortical Projection Neurons
16.3 Organization of the Neocortex
16.4 Trajectory of Migrating Neurons in the Developing Brain
16.5 Modes of Migration
16.6 Radial Migration in the Developing Human Neocortex
16.7 Factors that Regulate the Radial Migration of Cortical Neurons
16.8 Summary
References
Chapter 17. Radial Migration of Neurons in the Cerebral Cortex
17.1 Overview of Neuronal Migration During Cerebral Cortical Development
17.2 Patterns and Cellular Mechanisms of Radial Migration
17.3 Signaling Mechanisms Regulating Radial Migration
17.4 Radial Neuronal Migration and Human Neurodevelopmental Disorders
References
Chapter 18. Migration in the Hippocampus
18.1 Overview of Hippocampal Structure and Lamination
18.2 Developmental Specification of Hippocampal Fields
18.3 Migration of Cajal–Retzius Cells in the Hippocampus
18.4 Migration of Hippocampal Pyramidal Neurons
18.5 Migration of Hippocampal Interneurons
18.6 Migration of Neural Progenitors and Granule Cells in the Dentate Gyrus During Development
18.7 Conclusions
References
Chapter 19. Hindbrain Tangential Migration
19.1 Introduction
19.2 Tangential Migration: A Historical Overview
19.3 Molecular Mechanisms Controlling the Tangential Migration of Precerebellar Neurons
19.4 Molecular Mechanisms Controlling the Tangential Migration of Facial Motor Neurons
19.5 Ending Tangential Migration
19.6 Conclusion
Acknowledgments
References
Chapter 20. Tangential Migration: The Forebrain
20.1 Introduction
20.2 The Origin and Trajectory of Tangentially Migrating Cells in the Forebrain
20.3 Mechanisms That Guide Tangential Migration
20.4 Switch from Tangential to Radial Migration
20.5 Migration Defects and Disease: Lissencephaly
20.6 Future Directions
References
Chapter 21. Transcriptional Regulation of Tangential Neuronal Migration in the Vertebrate Hindbrain
21.1 Introduction
21.2 Breaking Boundaries: Transcriptional Regulation of Tangential Neuronal Migration Across Rhombomeres
21.3 Conclusions and Perspectives
Acknowledgments
References
Chapter 22. Postnatal Neurogenesis of the Forebrain
22.1 Introduction
22.2 Migration of Neuroblasts: Cell Autonomous Versus Extrinsic Factors
22.3 Radial Migration of Adult-Born Neurons and Their Integration
22.4 Hijacking Migratory RMS Neuroblasts
22.5 Outlooks
Acknowledgments
References
Chapter 23. Migration of Myelin-Forming Cells in the CNS
23.1 Introduction
23.2 Migratory Paths Followed by Oligodendrocyte Progenitor and Precursor Cells
23.3 Chemokinetic Factors: The Motility of Oligodendrocyte Precursors
23.4 Adhesion and Chemotactic Mechanisms: How the Movement of Oligodendrocyte Precursors Is Guided
23.5 Concluding Remarks
Acknowledgments
References
Chapter 24. Neuronal Migration and Brain Patterning
24.1 Cortical Development
24.2 The Borders of the Developing Pallium and the Generation of Tangentially Migrating Glutamatergic Neurons
24.3 CR Subtypes and Extrinsic Control in Regionalization of the Cerebral Cortex
24.4 CP Neurons and Their Role in Corticogenesis
24.5 Other Migrating Cells Generated at the Borders and Brain Patterning: The Example of Neural Crest Cells
24.6 Growth and Cell Fate Specification in Brain Patterning: Migration and Long-Range Patterning
24.7 Progenitor Domains, Tangential Migration of Glutamatergic Neurons and Cortical Evolution
24.8 Conclusions
See also
Acknowledgments
References
Chapter 25. Neuronal Migration of Guidepost Cells
25.1 An Introduction to Guidepost Cells
25.2 Role of Neuronal Migration in the Formation of the LOT
25.3 Hippocampal Cajal–Retzius Cells in the Formation of Axonal Connections
25.4 Migration of Neuronal Guidepost Cells in the Formation of Thalamocortical Connections
25.5 Neuronal Migration of Guidepost Cells in the Formation of the Corpus Callosum
25.6 Neuronal Migration of Guidepost Cells and Evolution of Brain Wiring
25.7 Toward an Integration of Migrating Guidepost Neurons in Normal and Pathological Brain Development
25.8 Conclusions
References
Chapter 26. Neuronal Migration Disorders
26.1 Introduction
26.2 Types of Malformations in NMD
26.3 Type 1 Lissencephaly
26.4 Mutations in Tubulin Subunits TUBA1A, TUBB2B, and TUBA8
26.5 Subcortical Band Heterotopia
26.6 Periventricular Heterotopia
26.7 Polymicrogyria
26.8 Cobblestone Cortical Malformation
26.9 Focal Cortical Dysplasia
26.10 Summary
Acknowledgments
References
III: Synaptogenesis
Chapter 27. Molecular Composition of Developing Glutamatergic Synapses
27.1 Introduction
27.2 Molecular Composition of Glutamatergic Synapses
27.3 Cellular Mechanisms of Transport of Molecules to Developing Synapses
27.4 Final Thoughts
Acknowledgments
References
Chapter 28. In Vivo Imaging of Synaptogenesis
28.1 Introduction
28.2 In Vivo Analysis of Synapse Development in the Neuromuscular Junction
28.3 Small Vertebrate Model Systems: Xenopus and Zebrafish
28.4 Visualizing Synaptogenesis in Mammals
28.5 Future perspectives
References
Chapter 29. Genetic Analysis of Synaptogenesis
29.1 Introduction
29.2 Studying Synaptogenesis in Genetic Model Organisms
29.3 Genetic and Molecular Tools for Large-Scale Genetic Screens
29.4 Perspective
References
Relevant Websites
Chapter 30. Activity-Regulated Genes and Synaptic Plasticity
30.1 The Role of Activity in Circuit Formation
30.2 Signaling from the Synapse to the Nucleus
30.3 Activity-Dependent Gene Expression
30.4 Activity-Regulated Genes that Modulate Synaptic Strength
30.5 Activity-Regulated Genes that Act in Synapse Addition and Elimination
30.6 Other Activity-Regulated Effector Genes
30.7 Posttranscriptional Regulation
30.8 Conclusions
References
Chapter 31. New Imaging Tools to Study Synaptogenesis
31.1 Introduction
31.2 Conventional Fluorescence Microscopy and Electron Microscopy
31.3 Recent Advances in Fluorescence Microscopy: Toward Super-resolution Microscopy
31.4 Recent Advances in Electron Microscopy: 3D Sectioning Techniques and Correlative Microscopy
31.5 New Developments in Genetically Encoded Photosensitive Tools
31.6 New Physical Tools to Culture Neurons
31.7 Conclusion
References
Chapter 32. Wnt Signaling
Abbreviations
32.1 Introduction
32.2 Wnts and Their Signaling Pathways
32.3 Regulation of Presynaptic Differentiation
32.4 Regulation of Postsynaptic Organization
32.5 Wnt Proteins as Antisynaptogenic Factors
32.6 Wnt Signaling and Activity-Mediated Synaptic Remodeling
Glossary
Acknowledgments
References
Relevant Websites
Chapter 33. Neurotrophins and Synaptogenesis
33.1 Introduction
33.2 Neurotrophins and the Integration of Circuits
33.3 Neurotrophin Signaling
33.4 Translation of Neurotrophic Effects into Synaptogenesis
33.5 Effects of Neurotrophins on the Inhibitory/Excitatory Balance
33.6 Specificity of Neurotrophin Actions
33.7 Conclusion and Perspectives
References
Chapter 34. Ephrins and Eph Receptors – Synaptogenesis and Synaptic Function
34.1 Introduction
34.2 Eph Forward Signaling in Synapse Formation and Spine Morphogenesis
34.3 Ephrin Reverse Signaling in Spine and Synapse Formation
34.4 Eph–Ephrin Signaling in Synaptic Plasticity
34.5 The Actions of Presynaptic Ephrins and Postsynaptic Ephs
34.6 The Actions of Presynaptic Ephs and Postsynaptic Ephrins
34.7 Modulation of Spine Morphology and Synaptic Plasticity by Eph–Ephrin Signaling at the Neuron–Glia Interphase
34.8 Regulation of Neuromuscular Junction Function by Eph–Ephrin Signaling
34.9 Conclusions and Perspectives
References
Chapter 35. Neuroligins and Neurexins
Abbreviations
35.1 Introduction
35.2 Along Came a Spider: Discovery of NRX and NL Proteins
35.3 Extensive Diversification: Gene and Protein Structures
35.4 Crystal Clear: Structural Insights into NL–NRX Interactions
35.5 Dynamic Modifications: Regulation of Alternative Splicing
35.6 Nonexclusive Partners: Complexes with Additional Synaptic Proteins
35.7 Acting Locally: Polarized Transport and Synapse-Specific Localization
35.8 More than Glue: Synaptic Functions of NL–NRX Complexes
35.9 From Synapses to Behavior: Disruption of the NRX–NL Complex in Neurodevelopmental Disorders
35.10 Twenty Years and on: Outlook
References
Chapter 36. Circuit Assembly in the Developing Vertebrate Retina
36.1 Introduction
36.2 Retinal Synaptic Laminae
36.3 Axonal and Dendritic Development
36.4 Synaptogenesis
36.5 Functional Assembly
Acknowledgments
References
Chapter 37. Synaptogenesis in the Adult CNS – Neocortical Plasticity
37.1 Neuronal Structural Plasticity in the Adult?
37.2 Lessons from In Vivo Structural Imaging in the Adult Neocortex
37.3 Molecular Aspects of Synapse Formation in the Adult
37.4 Conclusion
References
Chapter 38. Synaptogenesis in the Adult CNS – Hippocampus
38.1 Overview of the Hippocampus and Adult Neurogenesis in the Dentate Gyrus
38.2 Synaptogenesis in the Adult Hippocampus – Newborn Granule Cells
38.3 Synaptogenesis in the Adult Hippocampus – CA1 and CA3 Pyramidal Cells and Other Neurons of the Hippocampus
38.4 Conclusions
See also
Acknowledgments
References
Chapter 39. Synaptogenesis in the Adult CNS–Olfactory System
39.1 Introduction
39.2 Olfaction – A Central Sense Driving Behavior
39.3 Basic Architecture of the OB
39.4 Synaptogenesis in the Adult OB
39.5 Mechanisms of Synaptogenesis in the Adult OB
39.6 Future Perspective
Acknowledgments
References
Chapter 40. Synaptogenesis and Recovery from Cortical Trauma
40.1 Introduction
40.2 Functional Consequences of Cortical Damage
40.3 Axonal Sprouting
40.4 New Synapse Formation and Ultrastructural Changes After Cortical Injury
40.5 Functional Significance of Postinjury Synaptogenesis
40.6 Early Postlesion Events Leading to Initiation of Axonal Sprouting and Synaptogenesis
40.7 Role of Neuron–Astrocyte and Neuron–Glia Signaling in Cortical Injury
40.8 Regulation of Neurite Outgrowth
40.9 Arborization: Presynaptic Elements
40.10 Postsynaptic Elements
40.11 Rehabilitative Therapies
40.12 Concluding Remarks
References
IV: Developmental Sequences in the Maturation of Intrinsic and Synapse Driven Patterns
Chapter 41. GABA: A Multifacet Device that Exerts a Crucial Role in Brain Development
41.1 Introduction
41.2 GABA Depolarizes, Occasionally Excites Immature Neurons, and Produces a Rise of [Ca²+]I
41.3 Excitatory Actions of GABA are Mediated by a Developmental Expression of Chloride Cotransporters NKCC1 and KCC2
41.4 gabaergic Signals Develop Before Glutamatergic Ones in Many Brain Structures
41.5 The GABA-Glutamate Sequence in Other Brain Regions
41.6 A Parallel Developmental Sequence of Brain Patterns
41.7 An Abrupt Shift of [Cl−]I During Delivery Illustrates the Importance of Modulating GABA Actions
41.8 Activity-Dependent Plasticity of EGABA and Dynamic Chloride Regulation
41.9 Nonsynaptic Trophic Actions of GABA on Neuron Migration and Growth
41.10 General Conclusions
References
Chapter 42. Lessons from Zebrafish: Ion Channels Guide Neuronal Development
Abbreviations
42.1 Introduction
42.2 Existing Experimental Obstacles/Advantages of Zebrafish System
42.3 Activity and Development of Zebrafish Spinal Cord
42.4 An Unexplored Mechanism
42.5 Future Directions and Future Challenges
References
Chapter 43. Regulation of AMPA-Type Glutamate Receptor Trafficking
43.1 Introduction
43.2 Structure and Functions of AMPA Receptors
43.3 Synapse Development and AMPA Receptor Trafficking
43.4 Actin and Microtubule Organization in Neurons
43.5 AMPA Receptor Trafficking Along Microtubules in Dendrites
43.6 AMPA Receptor Trafficking Along the Actin Cytoskeleton in Dendritic Spines
43.7 Surface Trafficking of AMPA Receptors
43.8 Conclusion
Acknowledgments
References
Chapter 44. Pre- and Postsynaptic Assembly and Maturation: Principal Mechanisms and Coordination
Abbreviations
44.1 Synaptic Modules and Their Ultrastructure
44.2 Synapse Assembly and Maturation
44.3 Synapse Dynamics and Plastic Changes
44.4 Conclusions
References
Chapter 45. Cajal–Retzius and Subplate Cells: Transient Cortical Neurons and Circuits
45.1 Introduction
45.2 Cajal–Retzius Neurons
45.3 Subplate Neurons
45.4 Developmental Destiny of Cajal–Retzius and Subplate Neurons: Preservation or Disappearance
45.5 Conclusions and Perspectives
See also
Acknowledgments
References
Chapter 46. Chloride Homeodynamics Underlying Pathogenic Modal Shifts of GABA Actions
Abbreviations
Symbols
46.1 Developmental and Dynamic Shifts of Cl− Homeostasis Change GABA Actions
46.2 Pathological Models of Dynamic Cl− Homeostasis Perturbation
46.3 Pathological Models of Developmental Cl− Homeostasis Disorders
46.4 Pathological Models of Regenerating Immature Cl− Homeostasis Induced by Injury
46.5 Perspectives of Possible Involvement of Cl− Homeodynamics in Pathogenesis
46.6 Conclusion
References
Chapter 47. GABAergic Signaling at Newborn Mossy Fiber–CA3 Synapses: Short- and Long-Term Activity-Dependent Plasticity Processes
Abbreviations
47.1 Mossy Fiber Synapses
47.2 Co-release of Glutamate and GABA from MF Terminals
47.3 Criteria for Identifying Single MF-Evoked Responses
47.4 GABA is the Main Neurotransmitter Released from Immature MF Terminals
47.5 Presynaptic Modulation of GABA Release
47.6 Activity-Dependent Changes in Synaptic Efficacy
47.7 Conclusions
Acknowledgments
References
Chapter 48. BDNF and the Plasticity of Brain Networks During Maturation
48.1 Introduction
48.2 A Short Introduction to Neurotrophin Signaling Pathways
48.3 BDNF is a Target-Derived Messenger
48.4 BDNF is a Target-Derived Messenger for Activity-Dependent GABAergic Synaptic Plasticity in the Developing Brain
48.5 Conclusions
See also
Acknowledgments
Glossary
References
Chapter 49. Retinal Waves: Underlying Cellular Mechanisms and Theoretical Considerations
49.1 Introduction
49.2 How do We Record Retinal Waves?
49.3 Cellular Mechanisms Underlying Wave Generation in the Developing Retina
49.4 Retinal Waves are Under Homeostatic Control
See also
References
Chapter 50. Multimodal GABAA Receptor Functions on Cell Development
Nomenclature
50.1 Developmental Shifts of GABAA Receptor Subunit Composition
50.2 GABAA Receptor Function in Neurogenesis
50.3 GABAA Receptor Function on Migration
50.4 GABAA Receptor Function on Synaptogenesis
50.5 GABAA Receptor Function on Excitatory Neurotransmission
50.6 When Does Inhibitory GABAA Receptor-Mediated Neurotransmission Emerge?
50.7 Perspectives for Possible Involvement of Perturbations of Multimodal GABAA Receptor Development in Pathogenesis
50.8 Conclusion
See also
References
Chapter 51. Retinal Waves and their Role in Visual System Development
51.1 Introduction
51.2 Spatiotemporal Patterns of Retinal Waves
51.3 Influence of Waves on Retinal Development
51.4 Retinal Waves and Retinotopic Refinement
51.5 Retinal Waves and Eye-Specific Segregation
51.6 Retinal Waves and ON/OFF Segregation in the dLGN
51.7 Retinal Waves Influence the Developing Visual Cortex
51.8 Conclusions
References
Chapter 52. The Maturation of Firing Properties of Forebrain GABAergic Interneurons
52.1 Introduction
52.2 Interneuron Diversity
52.3 Embryonic Origins of Cortical Interneuron Subtypes
52.4 Postnatal Maturation of Interneuron Electrophysiology and Gene Expression
52.5 Activity-Dependent Postnatal Maturation of Cortical Interneuron Subtypes
52.6 Concluding Remarks
References
Chapter 53. Multiple Roles of KCC2 in the Developing Brain
53.1 Introduction
53.2 KCC2 and the CCC Family
53.3 Spatiotemporal Pattern of KCC2 Expression
53.4 Functional Regulation of KCC2
53.5 Functional Role of KCC2
Acknowledgment
References
Chapter 54. NKCC1 and Brain Maturation
54.1 Introduction
54.2 NKCC1 is a Key Prerequisite for GABAergic Depolarization
54.3 Expression, Regulation, and Modulation of NKCC1
54.4 Effects of NKCC1 on Brain Development
54.5 NKCC1 and Neonatal Epilepsy
54.6 NKCC1 During Adult Neurogenesis
54.7 Outlook and Final Remarks
References
Chapter 55. Maturation of Inhibitory Synaptic Transmission in the Spinal Cord: Role of the Brain Stem and Contribution to the Development of Motor Patterns
Abbreviations
55.1 Introduction
55.2 Development of the Locomotor Pattern
55.3 Development of Spontaneous Activity
55.4 Maturation of GABAA- and Glycine-Receptor-Gated Chloride Channels
55.5 Maturation of Chloride Homeostasis
55.6 Conclusion
References
Chapter 56. Calcium Signals Regulate Neurotransmitter Phenotype
56.1 Introduction
56.2 Calcium Spiking
56.3 Neurotransmitter Phenotype Specification – Intrinsic Determinants
56.4 Neurotransmitter Phenotype Plasticity
56.5 Mechanisms and Relevance of NPP
56.6 Perspectives
56.7 Summary
References
Index
Copyright
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Editors-in-Chief
Professor John L.R. Rubenstein, Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA
Professor Pasko Rakic, Duberg Professor of Neurobiology and Neurology, Director Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA
Section Editors
Professor Arturo Alvarez‐Buylla, Department of Neurological Surgery and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, School of Medicine, San Francisco, CA, USA
Professor Yehezkel Ben‐Ari, Institute of Neurobiology of the Mediterranean Sea (INMED) AND CEO of Neurochlore Company, INSERM (the French Institute of Health and Medical Research), Marseille, Department of the Bouches du Rhone
, France
Professor Kenneth Campbell, Divisions of Developmental Biology and Neurosurgery Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, OH, USA
Professor Hollis T. Cline, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA
Dr. François Guillemot, Division of Molecular Neurobiology MRC National Institute for Medical Research, London, UK
Professor Takao Hensch, Department of Molecular and Cellular Biology Harvard University, Cambridge, MA, USA
Professor Pat Levitt, Zilkha Neurogenetic Institute and Department of Cell and Neurobiology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
Dr Oscar Marín, Instituto de Neurociencias, CSIC and Universidad Miguel Hernández, Alicante, Spain
Professor Dennis D.M. O’Leary, Vincent J. Coates Chair in Molecular Neurobiology, Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA, USA
Professor Franck Polleux, The Scripps Research Institute, Dorris Neuroscience Center, La Jolla, CA, USA
Dr David H. Rowitch, University of California, San Francisco, CA, USA
Dr Gordon M. Shepherd, Department of Neurobiology, Yale School of Medicine, New Haven, CT, USA
Professor Helen Tager‐Flusberg, Department of Psychology and Department of Anatomy & Neurobiology, Boston University, Boston, MA, USA
Contributors
M.S. Airaksinen, University of Helsinki, Helsinki, Finland
S.A. Anderson, Weill Cornell Medical College, New York, NY, USA
E.S. Anton, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
S.L. Barrow, University of California, Davis, CA, USA
F. Beaubien, McGill University, Montréal, QC, Canada
R. Belvindrah, Institut Pasteur, Paris, France, CNRS, Paris, France, INSERM UMR-S 839, Paris, France, Université Pierre et Marie Curie, Paris, France, Institut du Fer á Moulin, Paris, France
Y. Ben-Ari, INMED, INSERM U901, Marseilles, France
F. Bielle, Institut de Biologie de l’École Normale Supérieure (IBENS), Paris, France, Institut National de la Santé et de la Recherche Médicale (INSERM) U1024, Paris, France, Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris, France
K. Boekhoorn, Utrecht University, Utrecht, The Netherlands
A.B. Booker, University of Connecticut, Storrs, CT, USA
U. Borello, CNRS-UMR 7592, Institut Jacques Monod, Université Paris Diderot, Paris, France
F. Bradke, German Center for Neurodegenerative Diseases (DZNE), Axonal Growth and Regeneration, Bonn, Germany
V. Castellani, University of Lyon, Lyon, France
M.V. Chao, New York University, New York, NY, USA
F. Charron, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada, University of Montreal, Montreal, QC, Canada, McGill University, Montreal, QC, Canada
A. Chedotal, Institut de la Vision, Paris, France
E. Cherubini, International School for Advanced Studies (SISSA), Trieste, Italy
A.D. Chisholm, University of California, San Diego, CA, USA
J.-F. Cloutier, McGill University, Montréal, QC, Canada
C.L. Cunningham, University of California, Davis, CA, USA
M.B. Dalva, Thomas Jefferson University, Philadelphia, PA, USA
F. de Castro, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain, Instituto Cajal-CSIC, Madrid, Spain
M. Demarque, University of California San Diego, La Jolla, CA, USA, CNRS UPR 3294, Gif-sur-Yvette, France
T.L. Dickendesher, The University of Michigan, Ann Arbor, MI, USA
T. Di Meglio, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
Y. Duan, The University of Michigan, Ann Arbor, MI, USA
R. Eavri, Massachusetts Institute of Technology, Cambridge, MA, USA
J. Falk, University of Lyon, Lyon, France
D.A. Feldheim, University of California, Santa Cruz, CA, USA
M.B. Feller, University of California at Berkeley, Berkeley, CA, USA
A. Filosa, Max-Planck Institute of Neurobiology, Munich-Martinsried, Germany
K.C. Flynn, German Center for Neurodegenerative Diseases (DZNE), Axonal Growth and Regeneration, Bonn, Germany
K.D. Foote, Lerner Research Institute, Cleveland, OH, USA
A. Fukuda, Hamamatsu University School of Medicine, Hamamatsu, Japan
T. Furukawa, Hamamatsu University School of Medicine, Hamamatsu, Japan
F.H. Gage, Salk Institute for Biological Studies, La Jolla, CA, USA
J.-L. Gaiarsa, INMED, INSERM U901, Université de Méditerranée, Université de La Méditerranée, Marseille, France
S. Garel, Institut de Biologie de l’École Normale Supérieure (IBENS), Paris, France, Institut National de la Santé et de la Recherche Médicale (INSERM) U1024, Paris, France, Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris, France
G. Gerlitz, NCI, NIH, Bethesda, MD, USA
D.A. Gibson, University of Southern California, Los Angeles, CA, USA
R.J. Giger, The University of Michigan, Ann Arbor, MI, USA
A. Griveau, CNRS-UMR 7592, Institut Jacques Monod, Université Paris Diderot, Paris, France, Howard Hughes Medical Institute, and Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, CA, USA
W.B. Grueber, Columbia University, New York, NY, USA
Z. He, Harvard Medical School, Boston, MA, USA
M.H. Hennig, University of Edinburgh, Edinburgh, UK
C.C. Hoogenraad, Erasmus Medical Center, Rotterdam, The Netherlands
C.A. Hübner, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany
L. Izzi, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada, University of Montreal, Montreal, QC, Canada
F. Jeanneteau, New York University, New York, NY, USA
D. Kerschensteiner, Washington University School of Medicine, St. Louis, MO, USA
R. Klein, Max-Planck Institute of Neurobiology, Munich-Martinsried, Germany
H. Komuro, Lerner Research Institute, Cleveland, OH, USA
Y. Komuro, Lerner Research Institute, Cleveland, OH, USA
A.R. Kriegstein, University of California, Davis, CA, USA
T. Kumada, Lerner Research Institute, Cleveland, OH, USA, Hamamatsu University School of Medicine, Hamamatsu, Japan
J.H. Leslie, Massachusetts Institute of Technology, Cambridge, MA, USA
G. Li, University of California, San Francisco, CA, USA
O. Llano, University of Helsinki, Helsinki, Finland
P.-M. Lledo, Institut Pasteur, Paris, France; CNRS, Paris, France
C. Lohmann, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
J.J. LoTurco, University of Connecticut, Storrs, CT, USA
C.S. Lu, Harvard Medical School, Boston, MA, USA
A. Ludwig, University of Helsinki, Helsinki, Finland
H.J. Luhmann, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany
L. Ma, University of Southern California, Los Angeles, CA, USA
S.J. Le Marchand, Thomas Jefferson University, Philadelphia, PA, USA
T.C. Martin, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
A.K. McAllister, University of California, Davis, CA, USA
D. McNeal, University of Kansas Medical Center, Kansas City, KS, USA
A. Mizrahi, The Hebrew University of Jerusalem, Jerusalem, Israel
F. Moya, Instituto de Neurociencias de Alicante (UMH-CSIC), Universidad Miguel Hernandez-Consejo Superior de Investigaciones Científicas, San Juan de Alicante, Spain
M. Munz, McGill University, Montreal, QC, Canada
K. Nakajima, Keio University School of Medicine, Tokyo, Japan
Y. Nakanishi, Hamamatsu University School of Medicine, Hamamatsu, Japan
E. Nedivi, Massachusetts Institute of Technology, Cambridge, MA, USA
S.B. Nelson, Brandeis University, Waltham, MA, USA
S.C. Noctor, University of California, Davis, CA, USA
R.J. Nudo, University of Kansas Medical Center, Kansas City, KS, USA
N. Ohno, Lerner Research Institute, Cleveland, OH, USA
B.W. Okaty, Harvard Medical School, Boston, MA, USA
T.J. Petros, Weill Cornell Medical College, New York, NY, USA
C.K. Pfeffer, University of California San Diego, La Jolla, CA, USA
A. Pierani, CNRS-UMR 7592, Institut Jacques Monod, Université Paris Diderot, Paris, France
S.J. Pleasure, University of California, San Francisco, CA, USA
F. Polleux, The Scripps Research Institute, La Jolla, CA, USA
J.E.A. Prince, McGill University, Montréal, QC, Canada
O. Reiner, The Weizmann Institute of Science, Rehovot, Israel
A.B. Ribera, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
F.M. Rijli, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
C. Rivera, University of Helsinki, Helsinki, Finland, Université de la Méditerranée, Aix-Marseille, France
E.S. Ruthazer, McGill University, Montreal, QC, Canada
P.C. Salinas, University College London, London, UK
P. Scheiffele, University of Basel, Basel, Switzerland
D. Schreiner, University of Basel, Basel, Switzerland
K. Sekine, Keio University School of Medicine, Tokyo, Japan
E. Sernagor, Newcastle University, Newcastle upon Tyne, UK
S.J. Sigrist, Free University Berlin, Berlin, Germany, Charité Universitätsmedizin Berlin, Berlin, Germany
C. Sotelo, Institut de la Vision, Paris, France, Instituto de Neurociencias, Miguel Hernandez University and CSIC, Alicante, Spain
N.C. Spitzer, University of California San Diego, La Jolla, CA, USA
A. Stanco, University of California, San Francisco, CA, USA
M. Stiess, German Center for Neurodegenerative Diseases (DZNE), Axonal Growth and Regeneration, Bonn, Germany
S.C. Suzuki, University of Washington, Seattle, WA, USA
H. Tabata, Keio University School of Medicine, Tokyo, Japan
N. Toni, University of Lausanne, Lausanne, Switzerland
P. Uvarov, University of Helsinki, Helsinki, Finland
M. Valdeolmillos, Instituto de Neurociencias de Alicante (UMH-CSIC), Universidad Miguel Hernandez-Consejo Superior de Investigaciones Científicas, San Juan de Alicante, Spain
D. Van Vactor, Harvard Medical School, Boston, MA, USA
L. Vinay, Centre National de la Recherche Scientifique (CNRS) & Aix-Marseille Université, Marseille, France
F. Wang, Duke University, Durham, NC, USA
C. Wichmann, Charité Universitätsmedizin Berlin, Berlin, Germany, University of Göttingen, Gottingen, Germany
R.O.L. Wong, University of Washington, Seattle, WA, USA
T. Yoshimatsu, University of Washington, Seattle, WA, USA
B. Zalc, Université Pierre & Marie Curie, Paris, France
C. Zhao, Salk Institute for Biological Studies, La Jolla, CA, USA
Introduction to Comprehensive Developmental Neuroscience
It is broadly accepted that understanding the genetic, molecular, and cellular mechanisms of neural development is essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information. By contrast, there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. Therefore, we embarked on the formidable task of assembling a novel resource entitled ‘Comprehensive Developmental Neuroscience.’ We hope that the books in this series will serve as valuable references for basic and translational neuroscientists, clinicians, and students.
To help with this enormous task, we invited leading experts in various subfields to select the subjects and invite appropriate authors. We were gratified by the number of busy scientists who accepted the invitation to write their articles. All the chapters have been peer reviewed by the Section Editors to ensure accuracy, thoroughness, and scholarship.
In the resulting three volumes, we cover a broad array of subjects on neural development. We organized the volumes chronologically according to the ordered steps in neural development. In addition, each volume is subdivided into three to four sections, each edited by world experts in these areas. The sections have 10–20 chapters that are written and illustrated by leading scientists.
This Volume in the series has 56 chapters devoted to migration (cell and axonal), the formation of neuronal connections, and the maturation of neural functions. This volume is subdivided into four sections. The first is on mechanisms that control the formation of axons and dendrites. The second is on the mechanisms that regulate cell migration that disperses specific subtypes of cells along highly defined pathways to specific destinations. The third section is on the regulation of synapse formation and maintenance during development; in addition, it has chapters on synaptogenesis in the mature nervous system in response to neurogenesis, neural activity, and neural trauma. The final section is on the developmental sequences that regulate neural activity, from cell-intrinsic maturation to early correlated patterns of activity.
Volume 1 in the series has 48 chapters devoted mainly to patterning and cell type specification in the developing central and peripheral nervous systems (CNS and PNS). This volume is subdivided into three sections. The first is on the mechanisms that control regional specification, which generate subdivisions of the nervous system. The second is on mechanisms that regulate the proliferation of neuronal progenitors and that control differentiation and survival of specific neuronal subtypes. The third section addresses the mechanisms controlling development of non-neural cells: astrocytes, oligodendroyctes, Schwann cells, microglia, meninges, blood vessels, ependyma, and choroid plexus.
Volume 3 in the series has 40 chapters devoted to the anatomical and functional development of neural circuits and neural systems, as well as chapters that address neurodevelopmental disorders in humans and experimental organisms. This volume is subdivided into three sections. The first is on the mechanisms that control the assembly of neural circuits in specific regions of the nervous system, and as a function of neural activity and critical periods. The second section concentrates on multiple aspects of cognitive development, particularly in humans. The final section addresses disorders of the nervous system that arise through defects in neural development, building on the principles that are addressed in earlier sections of the book.
John L.R. Rubenstein
Pasko Rakic
I
Formation of Axons and Dendrites
Chapter 1 Development of Neuronal Polarity In Vivo
Chapter 2 Role of the Cytoskeleton and Membrane Trafficking in Axon–Dendrite Morphogenesis
Chapter 3 Axon Growth and Branching
Chapter 4 Axon Guidance
Chapter 5 Roles of Eph–Ephrin Signaling in Axon Guidance
Chapter 6 Axon Guidance
Chapter 7 Nonconventional Axon Guidance Cues
Chapter 8 Axon Regeneration
Chapter 9 Axon Maintenance and Degeneration
Chapter 10 Dendrite Development
Chapter 11 Dendritic Development
Chapter 1
Development of Neuronal Polarity In Vivo
F. Polleux, The Scripps Research Institute, La Jolla, CA, USA
Outline
1.1 Introduction
1.2 Axon Initiation In Vitro Versus In Vivo
1.2.1 Axon Initiation In Vitro
1.2.2 Axon Initiation In Vivo
1.3 Distinction Between Cues Regulating Axon Specification Versus Axon Growth
1.4 Extracellular Cues Regulating Neuronal Polarization and Axon Initiation
1.4.1 Netrin-1 and Wnt Control Axon Initiation in C. elegans
1.4.2 Polarized Emergence of the Axon in Retinal Ganglion Cells of Xenopus
1.4.3 Extracellular Cues Underlying the Emergence of Axon and Dendrites in Mammalian Neurons
1.5 Intracellular Pathways Underlying Neuronal Polarization
1.5.1 Role of Local Protein Translation and Degradation for Axon Specification and Axon Growth
1.5.2 Role of Cytoskeletal Dynamics in Axon Initiation and Growth
1.5.3 Major Signaling Pathways Involved in Axon Initiation and Growth
1.5.3.1 LKB1 and its Downstream Kinases SAD-A/B and MARK1-4
1.5.3.2 PAR3–PAR6–APKC
1.5.3.3 Ras- and Rho-Family of Small GTPases
1.5.3.4 PI3-Kinase and PTEN Signaling during Axon Specification
1.5.3.5 AKT/Protein Kinase B
1.5.3.6 GSK3 and Axon Specification
References
1.1 Introduction
The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system (CNS). Dendrites and axons are molecularly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon that makes presynaptic contacts onto target cells. This chapter reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to polarize and form a single axon and multiple dendrites during development. This question has received much attention over the past three decades using mainly in vitro approaches, where neurons from distinct parts of the developing mammalian brain can be dissociated and cultured to get single cell resolution. Remarkably, neurons can polarize to form a single axon and multiple dendrites, and later establish functional synaptic contacts in these reductionist conditions. This approach became, and remains, the dominant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro. At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro axon initiation and elongation is thought to reflect the intrinsic ability of neurons to polarize in the absence of relevant extracellular cues. However, extracellular cues have been shown to play an important role during neuronal polarization in vivo. In this chapter, we focus on our current understanding of the complex interplay between extracellular cues and intracellular signaling pathways underlying the emergence of axon and dendrite during neuronal polarization in vivo.
1.2 Axon Initiation In Vitro Versus In Vivo
1.2.1 Axon Initiation In Vitro
Historically, the advent of in vitro dissociated neuronal cultures provided an experimental template for improving our understanding of the cell biology of neuronal polarity, including the specification of the molecular identity of axon and dendrite. Pioneering work using these cultures established a paradigm in which isolated neurons in culture can adopt spatially and functionally distinct dendritic and axonal domains (Craig and Banker, 1994; Goslin and Banker, 1989). Careful analysis of these cultures led to the observation that cultured hippocampal neurons transition through several stages, from freshly plated stage 1 cells bearing immature neurites to stage 5 cells that exhibit mature axons, dendrites, dendritic spines, and functional synapses (Craig and Banker, 1994; Dotti et al., 1988). It should be noted that in the classical E18 rat hippocampal cultures, most plated cells were polarized postmitotic neurons before dissociation; therefore, neuronal polarization using this in vitro model likely corresponds to the repolarization of previously polarized neurons in vivo. It is therefore important to keep in mind that molecular manipulations in this in vitro model act on previously polarized neurons that may retain some aspects of polarization, which can be critical for interpreting the results. Recent advances in the techniques allowing the manipulation of gene expression more specifically in neural progenitors, such as in utero or ex utero cortical electroporation (Hand et al., 2005; Hatanaka and Murakami, 2002; Saito and Nakatsuji, 2001; Tabata and Nakajima, 2001), provide a paradigm to (a) manipulate gene expression in progenitors, that is, before neuronal polarization occurs upon cell cycle exit and (b) visualize the earliest stages of neuronal polarization in a contextual cellular environment, that is, in organotypic slices or intact embryonic brain (Barnes et al., 2007; Calderon de Anda et al., 2008; Hand et al., 2005).
1.2.2 Axon Initiation In Vivo
Neuronal polarization can be divided into several specific steps in vivo. On cell cycle exit, mammalian neurons usually migrate over a long distance before reaching their final destination. In vivo, most neurons undergo axon–dendrite polarization during migration. While migrating, neocortical pyramidal neurons (PN) form a leading process and a trailing process, each becoming the axon or the dendrite (Figure 1.1). Careful examination of the morphological transition between neural progenitors and postmitotic neurons reveals that neurons can inherit their axon and dendrite polarity directly from the apicobasal polarity of their progenitors. This is the case for retinal ganglion cells and bipolar cells in the developing vertebrate retina (Hinds and Hinds, 1978; Morgan et al., 2006; Zolessi et al., 2006, reviewed in Barnes and Polleux, 2009). In other neuronal subpopulations undergoing long-range migration, neuronal morphogenesis undergoes extensive stereotypical changes, leading to polarized outgrowth of their axon and dendrites. This is the case for cerebellar granule neurons (CGN) as well as cortical and hippocampal PN, two of the best-studied models of neuronal polarization (Gao and Hatten, 1993; Hatanaka and Murakami, 2002; Komuro et al., 2001; Noctor et al., 2004; Rakic, 1971, 1972; Shoukimas and Hinds, 1978). Both CGN and PN acquire their axon–dendrite polarity from the polarized emergence of their trailing and leading processes, respectively, during migration (reviewed in Barnes and Polleux 2009). Precise examination of the process dynamics occurring shortly after cell cycle exit in dorsal telencephalic progenitors suggest that there is often a slight delay between the trailing process formation (axon initiation), which frequently precedes leading process formation (Calderon de Anda et al., 2008; Hand and Polleux, 2011). However, one thing is clear for both PN and CGN: axon formation starts before or during radial migration. Interestingly, different neuronal populations display distinct modes of axon formation, which reflect their mode of migration, lineage, and type of axon projection. For example, cortical interneurons, which will form axons projecting only locally within the cortex, originate from the ventral telencephalon and have to migrate over very long distances before initiating their axon after reaching their final destination in the cortex (Bortone and Polleux, 2009; Cobos et al., 2007; Yamasaki et al., 2010). Even though the precise mechanisms underlying the emergence of the axon of cortical interneurons are currently unknown, the striking difference with radially migrating pyramidal cortical neurons, which initiate axon formation during migration, leads to the hypothesis that their ability to form an axon is inhibited during tangential migration and/or that axon initiation in cortical interneurons depends on factor(s) present only in their final environment, the cortex.
Figure 1.1 Axon development in the neocortical pyramidal neurons. (a) During mouse corticogenesis, from embryonic day E11 to P1, neuronal polarization occurs rapidly on cell cycle exit (see more details in Figure 1.2) when neurons (green) transition from a multipolar morphology to a bipolar morphology by forming a leading process (future apical dendrite), which drives radial migration and a trailing process, which becomes the axon. Once neurons reach their final position, they undergo extensive dendritic branching. (b) At early postnatal stages (P1–P7), the axon of pyramidal neurons are guided either laterally (for corticofugal projections of layer 5/6) or medially (for callosal projection of layer 2/3 and 5). (c) On reaching their final target, axons undergo extensive, layer-specific branching concomitant with synaptogenesis. For example, callosal axons branch both ipsilaterally and contralaterally in layer 5 and layer 2/3 (green axons).
As discussed later in the chapter, an emerging concept from recent work done primarily in C. elegans suggests that in vivo, the ‘symmetry-breaking’ events that lead to the emergence of the dendrite and the axon require the ability of postmitotic neurons to sense gradients of extracellular cues, leading to the asymmetric activation of signaling pathways underlying the emergence of the axon. This data is supported by recent evidence in mammals showing that extracellular cues such as TGFß plays a role in axon specification in vivo by triggering noncanonical Par6-dependent signaling downstream of TGFß-receptor activation (Yi et al., 2010).
1.3 Distinction Between Cues Regulating Axon Specification Versus Axon Growth
Most studies published over the past two decades in this field have been performed using in vitro approaches. The classic paradigm for confirming the regulatory role of a gene in neuronal polarity is to show that downregulation of its expression using shRNA technology or gene knockout technology is required for axon formation. These experiments are typically done using both staining with axon-specific makers and measurement of neurite length because the axon usually grows 5–10 times faster than do neurites becoming dendrites. However, this type of evidence may not be sufficient to distinguish unambiguously an effector of axon specification from a molecule simply required for axon growth (Jiang et al., 2005). Conversely, showing that overexpression or overactivation of a candidate molecule leads to the emergence of multiple neurites, displaying the molecular identity of an axon is generally used to suggest that this molecule is sufficient to confer axon identity. However, this approach is limited by the fact that it relies on overexpression, which can be complicated by abnormal activation of a pathway normally not involved in axon specification or neuronal polarity. Recent technical advances allow the manipulation of gene expression in vivo by in utero cortical electroporation in rodent cortex or cerebellum (Famulski et al., 2010; Saito and Nakatsuji, 2001) or transgenic approaches in Xenopus (Zolessi et al., 2006). Therefore, a more biologically relevant validation of the function of a candidate gene during neuronal polarization often includes testing its requirement using gene knockout or shRNA-mediated knockdown technologies or the analysis of conventional or conditional knockout in combination with in utero electroporation allowing single cell resolution analysis of axon formation (Barnes et al., 2007; Shelly et al., 2007; Yi et al., 2010).
1.4 Extracellular Cues Regulating Neuronal Polarization and Axon Initiation
1.4.1 Netrin-1 and Wnt Control Axon Initiation in C. elegans
Is there any in vivo evidence for the role of extracellular cues in the specification of neuronal polarity? Important progress in our understanding of the molecular and cellular mechanisms specifying axon initiation during neuronal polarization has been made using the C. elegans model. This pioneering work has markedly enhanced our understanding of how extracellular cues instruct axon initiation in vivo. The neurons of the nematode have a stereotyped morphology, for example, specific projections along the dorsoventral and anterior–posterior body axes. Elegant experiments have identified an extracellular cue, UNC-6 (Netrin), along with its receptor UNC-40 (DCC), as a critical gene orchestrating axon initiation in vivo (Adler et al., 2006). This work also identified downstream proteins in this pathway, including (mammalian orthologs are shown in parenthesis when established) AGE-1 (phosphoinositide-3 kinase – PI3K), DAF-18 (PTEN), UNC-34 (Enabled), CED-10 (Rac), UNC-115/AbLIM, and MIG-10/lamellipodin. The current model for the relationship between these genes and UNC-6/netrin signaling involves DAF-18’s limitation of AGE-1 activity following UNC-40/DCC stimulation and the asymmetric recruitment of MIG-10/lamellipodin to the plasma membrane. This recruitment requires activated CED-10/Rac direct binding to MIG-10/lamellipodin and the involvement of the PAK-like kinase, Pak-1 (Adler et al., 2006). The involvement of a kinase in cytoskeletal rearrangement is consistent with the similar role of MIG-10/lamellipodin and the likely mechanism under which it operates once recruited to the plasma membrane to stimulate directed neurite outgrowth. Another regulator thought to act in concert to drive filopodial formation with MIG-10/lamellipodin is the Enabled homolog, UNC-34 (Chang et al., 2006). Finally, SLT-1 (Slit) is another extracellular cue that likely acts through MIG-10 recruitment (Chang et al., 2006) to control neuronal polarization.
Two other studies have identified the diffusible signal Wnt and its receptor as critical regulators of axon specification and neuronal polarity (Hilliard and Bargmann, 2006; Prasad and Clark, 2006). In addition to identifying loss of function for Lin-44 (Wnt) and its receptor Lin-17 (Frizzled – Fzl), one of the screens identified VPS-35, a component of retromer complex that regulates vesicular traffic and is required for proper Wnt secretion (Pan et al., 2008; Prasad and Clark, 2006).
1.4.2 Polarized Emergence of the Axon in Retinal Ganglion Cells of Xenopus
Careful live imaging experiments of Xenopus retinal ganglion cell polarization revealed that polarized axon outgrowth requires some unidentified extracellular cues present in the basal lamina (Randlett et al., 2011; Zolessi et al., 2006). The axon of developing RGCs normally grows on the basal side of the neuron. In a mutant called Nok, characterized by the absence of retinal pigmented epithelium, some postmitotic RGC neurons show a defective polarized outgrowth of their axon on the apical side along the now-exposed basal lamina. In this context, the polarized emergence of the axon on the basal side of the RGC is correlated with the position of the centrosome, Par3, and the apical complex (containing at least atypical protein kinase C (aPKC), β-catenin, and F-actin) on the apical side of the cell where the dendrite will emerge. Taken together, this work strongly suggests that (a) the basal lamina contains some important extracellular cues playing a role in the polarized emergence of the axon of RGC neurons and that (b) RGC neurons inherit the intrinsic apicobasal polarity of their progenitor at least with regard to the Par3/aPKC components of the polarity complex.
Recently, a signaling cascade has been linked to potential extracellular cues regulating axon initiation in vivo (Barnes and Polleux, 2009; Barnes et al., 2008). Conditional deletion of LKB1 in pyramidal cortical neurons (also called Par4 or STK11) demonstrated that LKB1 is required for axon initiation in cortical neurons but does not impact their radial migration (Barnes et al., 2007). Structure/function analysis indicates that phosphorylation of LKB1 at Serine 431 is required for its function in axon specification (Barnes et al., 2007), and Shelly et al. linked this phosphorylation to the ability of extracellular cues such as BNDF to stimulate cAMP production and protein kinase A (PKA)-dependent phosphorylation of S431 in the nascent axon (see below for details; Shelly et al., 2007, 2010, 2011).
1.4.3 Extracellular Cues Underlying the Emergence of Axon and Dendrites in Mammalian Neurons
Several lines of evidence suggest that extracellular cues can direct the polarized emergence of the axon and the dendrites both in vitro and in vivo. One paradigm involves dissociated cortical or hippocampal PN plated on striped substrates coated with two different cell adhesion molecules (e.g., laminin and NgCAM, reviewed in Barnes and Polleux, 2009). The first immature neurite of E18 hippocampal neurons, which contacts the boundary between two stripes, systematically becomes the axon. This occurs regardless of the fact that the initial outgrowth of immature neurites occurred on laminin or NgCAM, suggesting that immature neurites can detect changes in the nature of the extracellular substrate rather than the absolute nature of the novel substrate they are encountering (Esch et al., 1999). Using a similar approach, Shelly and colleagues showed that neurites of immature hippocampal neurons growing on a patterned substrate can detect the presence of brain-derived neurotrophic factor (BDNF), which plays an instructive role in axon specification because the first neurite contacting a BDNF stripe systematically becomes the axon (Shelly et al., 2007). The effect of BDNF on axon specification requires cAMP-dependent PKA activation and phosphorylation of LKB1 in position 431 by PKA (Shelly et al., 2007, 2010), suggesting that LKB1 phosphorylation on S431 acts as a detector of neuronal symmetry breaking by extracellular cues such as BDNF in this in vitro context.
The overlay assay is an in vitro assay developed to detect the existence of putative extracellular cues playing a role in cortical axon guidance and neuron polarization. This rather simple assay involves plating fluorescently labeled dissociated cortical neurons onto cortical slices to test whether polarized axon emergence in vivo is mainly the result of asymmetric activation of intracellular effectors (maybe inherited by progenitors) or if extracellular cues can play a role in axon specification. Polleux et al. have demonstrated that scenario 2 is the most likely because only a couple of hours after plating, the vast majority of cortical neurons displayed a single, short axon directed ventrally toward the ventricle (Polleux et al., 1998) as observed for radially migrating neurons in vivo. These authors went on to demonstrate that the class 3 secreted semaphorin, Sema3A, which is enriched in the most superficial part of the cortical wall (the top of the cortical plate), plays a role in repulsing axon initiation ventrally toward the ventricle (Polleux et al., 1998). More recently, Sema3A was shown to also regulate the polarized emergence of the leading process/apical dendrite both in the overlay assay, that is, independently of radial migration where it requires cGMP production and PKG activation (Polleux et al., 2000) and also in vivo during radial migration (Chen et al., 2008). Interestingly, Sema3A can play a role in the specification of dendritic identity by activating a cGMP-dependent pathway involving activation of cGMP-gated calcium channels (Nishiyama et al., 2011) and also by repressing axonal identity in a LKB1-dependent manner (Shelly et al., 2007, 2010, 2011; see Figure 1.2).
Figure 1.2 Extracellular signals regulate axon and dendrite specification in neocortical pyramidal neurons (PN). Time-lapse analysis has revealed that polarization of axodendritic polarity in PN occurs in vivo in a stepwise manner on cell cycle exit: following asymmetric division of radial glial cells (step 1) or intermediate progenitors in the subventricular zone (SVZ) (not shown) recently generated postmitotic neurons first form transient, dynamic neurites (multipolar stage; step 2). Axon specification occurs when a trailing process (TP) is stabilized (red) either before (step 3) or after the formation of a leading process (LP) in neurons engaging radial translocation (step 4). On reaching their final destination at the top of the cortical plate (CP) (step 5), neurons detach from the radial glial scaffold and start an extensive program of axon growth (see Figure 1.1) and dendritic branching concomitant with synaptogenesis (step 6).
Recently, TGFß signaling was shown to be required for the polarized emergence of the axon of radially migrating PN in vivo (Yi et al., 2010; Figure 1.3). TGFß ligands are expressed in the germinal zone of the cortex, where they could act as an instructive ‘ventral’ cue for the polarized emergence of the axon in multipolar neurons before engaging radial migration. In vitro experiments demonstrated that local application of TGFß on a single neurite in immature Stage 1 cortical neurons is sufficient to trigger fast axonal extension (Yi et al., 2010). Importantly, conditional genetic deletion of TGFß receptor 2 expression leads to the production of neurons without trailing process/axon in vivo. One noticeable difference with the conditional ablation of LKB1 (see below), which also leads to the absence of trailing process/axon formation but not radial migration defects, is that TGFß receptor 2 conditional deletion leads to retardation of radial migration in a subset of cortical neurons (Yi et al., 2010).
Figure 1.3 Intracellular pathways underlying axon specification in response to extracellular cues in vivo. As shown in Figure 1.2, recent data (Yi et al. 2010) provided evidence that TGFß receptor activation is required for axon specification/trailing process stabilization in vivo. This work also suggested that TGFß receptor signaling in the context of axon specification required a ‘noncanonical’ branch of TGFß involved in EMT, which triggers Par6 phosphorylation by TGFß receptor 2 and recruits the ubiquitin ligase Smurf1 and locally degrades RhoA, three steps previously shown to be required for axon specification. Another kinase previously shown to be required in vivo for axon specification is LKB1 (Par4), which is phosphorylated on S431 specifically in the axon in response to several signaling pathways (PKA, p90RSK, or aPKC). LKB1 phosphorylates and activates several other kinases, including SAD-A/B kinases, which have been shown to be required for axon specification in vivo. The actual link between TGFß receptor/Par6/Smurf1/RhoA and the LKB1/SAD kinase pathway is currently unknown but might involve direct interaction between Par6 and LKB1 or phosphorylation of LKB1 by aPKC, which is known to form a complex with Par6. The downstream effectors of SAD kinases and other LKB1-dependent kinases are currently unknown but might involve local phosphorylation of microtubule-associated proteins such as Tau or MAP1b but probably involve many other effectors, all involved in axon specification. Proteins indicated in red have been shown to be required in vivo for axon specification, whereas proteins indicated in orange have only been studied in dissociated neuronal cultures in vitro.
The authors went on to demonstrate that TGFß receptor function during axon specification requires the phosphorylation of Par6 on S435 previously shown to mediate epithelial to mesenchymal transition (EMT; Ozdamar et al., 2005). As discussed later in the chapter, this ‘noncanonical’ TGFß receptor-dependent signaling represents an attractive in vivo signaling pathway for axon specification since it is known to involve recruitment of the ubiquitin ligase Smurf1 that induces local degradation of RhoA during EMT, which have both previously been involved in axon specification (Schwamborn et al., 2007a,b). Therefore, these results suggest that neuronal polarization might have coopted signaling pathways regulating EMT for the purpose of axon specification.
Overall, this work suggests that the polarized emergence of a single axon/trailing process and the apical dendrite/leading process are controlled at least in part by extracellular cues such as TGFß and Sema3A, respectively, expressed in a graded manner along the neuron’s migratory path (Figure 1.2). More work needs to clarify if other extracellular cues are required for the polarized emergence of axons and dendrites in diverse neuronal cell types and how these extracellular cues mediate their effects on the specification of the unique molecular identity of axons and dendrites.
1.5 Intracellular Pathways Underlying Neuronal Polarization
1.5.1 Role of Local Protein Translation and Degradation for Axon Specification and Axon Growth
Spatial regulation of protein expression by selective degradation has been demonstrated in several contexts during neuronal development, including axonal pruning (Watts et al., 2004), various aspects of axon guidance (Bloom et al., 2007; Campbell and Holt, 2001; DiAntonio et al., 2001; Lewcock et al., 2007), synapse formation (DiAntonio et al., 2001; Nakata et al., 2005), synapse maintenance (Aravamudan and Broadie, 2003; DiAntonio et al., 2001; Ehlers, 2003; Speese et al., 2003), and synapse elimination (Ding et al., 2007, reviewed in DiAntonio and Hicke, 2004). Acute treatment with the proteosome inhibitor lactacystin blocks axogenesis in dorsal root ganglion cells (Klimaschewski et al., 2006). Furthermore, more prolonged inhibition of protein degradation with lactacystin leads to the formation of multiple axons (Yan et al., 2006). The protein kinase AKT, which we previously described as critical for neuronal polarity, appears to undergo selective degradation (Yan et al., 2006). In fact, this degradation selectively targets the inactive pool of AKT in neurites, resulting in a net enrichment of AKT in a single process that contains active AKT, the nascent axon. This phenomenon is consistent with the negative feedback signal model proposed by Kaibuchi and colleagues (Arimura and Kaibuchi, 2007) to explain axon specification of a single axon during neuronal polarization. Schwamborn et al. showed that the small GTPase Rap1b is regulated by a similar scheme because the active form of Rap1b is spared from degradation and ultimately enriched in the axon (Schwamborn et al., 2007b). In this case, the ubiquitin ligase acting on Rap1b is Smurf2, whereas the related Smurf1 appears to affect only neurite outgrowth. Additional work has demonstrated that an interaction between Smurf2 and the polarity scaffold PAR3 must exist for proper neuron polarization (Schwamborn et al., 2007a). This finding appears to be related to PAR3 targeting of Smurf2 to the axon because perturbation of the interaction of either PAR3–Smurf2 or PAR3–KIF3A results in Rap1b increase in all neurites. The converse situation exists for LIM kinase (LIMK) because levels of this protein must be reduced for axon initiation in vitro (Tursun et al., 2005). Future experiments should clarify the molecular mechanisms regulating the function of Smurf1/2 ubiquitin ligases in axon specification in vivo especially in the context of TGFß signaling (Yi et al., 2010).
1.5.2 Role of Cytoskeletal Dynamics in Axon Initiation and Growth
Appropriate regulation of the actin and microtubule cytoskeleton is critical for neuronal polarization and has been the focus of numerous studies. Experiments using the actin-destabilizing agents, lactrunculin B and cytochalasin D, indicate that remodeling of the actin-based cytoskeleton is an important regulatory step in axon formation (Bradke and Dotti, 1997). Specifically, actin depolymerization localized to a single neurite in unpolarized stage 2 hippocampal neurons is sufficient to confer axonal identity. A proposed mechanism is that loose actin filaments allow the egress of microtubules and lead to rapid elongation of a given neurite, perhaps outpacing the transport of negative regulators of axonal identity. The idea of cellular asymmetries being reinforced by localized microtubule stabilization and invasion proposed by Kirschner and Mitchison (1986) was elegantly demonstrated using a photoactivatable form of the tubulin-stabilizing compound taxol, which can direct axonal specification to a single immature neurite (Witte et al., 2008). Collectively, these results suggest that a dynamic equilibrium between actin depolymerization and microtubule stabilization might play a role in specifying axonal initiation and axonal identity. Future investigations will need to identify the effectors regulating this balance locally and also characterize how specific upstream signaling pathways might regulate the spatial and temporal regulation of these cytoskeletal dynamics.
1.5.3 Major Signaling Pathways Involved in Axon Initiation and Growth
1.5.3.1 LKB1 and its Downstream Kinases SAD-A/B and MARK1-4
A pioneering genetic screening performed by Kemphues and colleagues in the late 1980s identified six Par genes encoding distinct protein families. Many studies have since demonstrated that invertebrate and vertebrate Par genes play critical roles in epithelial cell polarity during development as well as in the context of cell transformation and metastasis (Goldstein and Macara, 2007; Kemphues et al., 1988). Although this pathway is critical to polarity in many species, the signal linking this pathway to extracellular cues has remained elusive. The furthest upstream component known in this cascade is an evolutionarily conserved kinase named LKB1 or PAR4. LKB1 translocates from the nucleus and is activated by heterodimerization with one of two related pseudokinases known as Strad-α and -ß (Dorfman and Macara, 2008). In addition to binding Strad, LKB1 function in neuronal polarity requires its phosphorylation at S431, a target of both PKA and p90RSK kinases (Collins et al., 2000; Sapkota et al., 2001), and this phosphorylation can be triggered by extracellular cues such as BDNF (Shelly et al., 2007; Figure 1.2). This event might be mediated partly by cues providing chemotactic attraction of radially migrating neurons toward the cortical plate such as Sema3A (Chen et al., 2008; Polleux et al., 2000) or by other extracellular cues, including neurotrophins (NTs) such as BDNF/NT4/NT3 (Shelly et al., 2007), Netrin (Adler et al., 2006), FGFs, or any other cues that can activate cAMP-dependent PKA or p90 RSK (RSK1-3). At this point, we can speculate that any other presently uncharacterized serine/threonine PKA able to phosphorylate S431 on LKB1 might mediate the polarizing function of extracellular cues found in different developing brain regions (Barnes and Polleux, 2009). Future investigations will identify the relevant extracellular cues and the corresponding signaling pathways triggering phosphorylation of LKB1 in position S431, thereby specifying the axon in developing cortical PN in vivo.
Once LKB1 is activated by binding to its necessary coactivator Strad-α and S431 phosphorylation occurs (only in the neurite becoming the axon), LKB1 phosphorylates SAD-A/B kinases (and probably microtubule affinity-regulated kinases, MARK1-4; Matenia and Mandelkow, 2009), which are required for axon specification partly by phosphorylating microtubule-associated proteins (MAPs) such as Tau. On the basis of the function of SAD kinases in presynaptic vesicular clustering in C. elegans (Crump et al., 2001), we can hypothesize that SAD-A/B kinases might also specify axon identity by directing presynaptic vesicular trafficking in the neurite becoming the axon. Most important, genetic deletion of LKB1 in cortical PN prevents axon formation, whereas overexpression of LKB1 and its coactivator Strad in neural progenitors or LKB1 alone in postmitotic cells is sufficient to lead to the formation of multiple axons (Barnes et al., 2007; Shelly et al., 2007).
Experiments in Xenopus laevis suggested that LKB1 may regulate aPKC inactivation of glycogen synthase kinase 3 (GSK3)ß (Ossipova et al., 2003), two proteins involved in neuronal polarity (see below). However, at this point, the exact contribution of LKB1 in adenomatous polyposis coli (APC)/GSK3 function in neuronal polarity is poorly understood. LKB1 also phosphorylates and activates a family of 13 PKAs related to the C. elegans PAR1 protein (Lizcano et al., 2004). To date, three of these have been implicated in regulating axon formation: SAD-A and SAD-B kinases as well as MARK-2 (microtubule affinity regulating kinase-2; also called Par1b). RNAi knockdown of SAD kinases partially abrogates the ability of LKB1 overactivation to induce multiple axon formation in cortical neurons, indicating that