EMBRYOLOGY OF HEAD & NECK III Endodermal Pouches and Derivatives, Development of the Eye

Lillian B. Nanney, Ph.D. am) December 2, 2003 (11:00

Moore & Dalley: Clinically Oriented Anatomy, 4th ed.: pp. 1033-1034, 1036-1038, 1059-1060, 1072; Clinical Cases 8.6, 8.8, 8.16, 8.17 Moore & Persaud: The Developing Human, 6th ed. pp. 222-235 Sulik/Bream: Embryo Images (CD-ROM): Head & Neck plates 8, 18, 21, 22, 24 Sadler: Langman's Medical Embryology, 8th ed: 352-357, 359, 362-366 9th ed: 372-375, 378-3779, 382-386, 415-422, 424 Agur: Grant's Atlas of Anatomy, 10th ed.: 669 Dalley: Frank H. Netter, M.D., Atlas of Clinical Anatomy (CD-ROM), ver. 2.0: Plates C510-514; C528-529 3rd ed: 72 Cochard: Netters Atlas of Human Embryology: p. 66,67, 216-222, 234, 242, 243

Objectives: As a result of attending the audiovisual presentations, reading/viewing the textbook, and class notes, and comparisons to adult anatomy, a VMS I should understand and be able to: 1. Discuss the expected derivatives from each of the 5 pharyngeal pouches. 2. Explain the genesis and locations of branchial cysts/fistulas in the neck region. 3. Describe the migratory pathway and clinical implications for endodermal tissue that differentiates into thyroid tissue. 4. Use embryological perspectives to explain the ectopic location of parathyroid tissue. 5. The tongue is a unique organ innervated by 5 cranial nerves. Use embryology to explain the complexities of tongue innervation (general sensation, taste, motor). 6. Discuss the interrelationships of the neuroectoderm, mesoderm, and surface ectoderm during eye development 7. Use the developmental plan of the eye to explain coloboma, retinal detachment,

Review Pharyngeal (Branchial, Visceral) Arches typically develop a cartilaginous bar that stiffens the arch mesoderm that develops into muscles that move the skeletal parts nerves to structures associated with that arch an aortic arch artery that supplies that arch an endodermal pocket (diverticulum) develops posterior to each arch

I. Development of the Floor of the Mouth and Oropharynx

A. Tongue Development at the 4th week, inside mesoderm of the 1st arch proliferates into 2 lateral lingual swellings 1 median swelling - the tuberculum impar these rounded hills beneath the surface continue to grow and fuse forming the anterior 2/3rds of the tongue sensory innervation to its mucosa is derived from Vc - nerve of the 1st arch later the undersurface of the tongue degenerates leaving only a frenulum if many cells fail to regress - ankyloglossia, a tongue-tied condition will be present Mesoderm from the occipital somites that is innervated by CN XII early in its development begins a long migratory course that brings it through the neck and into position beneath the primitive tongue. Microglossia (small tongue) may be caused by the arrival of too little mesodermal tissue or the failure of the lingual swellings to proliferate. Macroglossia (too large of a tongue) is the opposite circumstance but is more problematic since it can significantly hinder phonation and breathing. B. Caudal to the Tongue Hypobranchial Eminence - another median swelling forms from the internal mesoderm of 2nd, 3rd, and 4th arch subsequently becomes the posterior 1/3rd of tongue and valleculae sensory innervation remains as the IX - nerve of the 3rd arch Epiglottis - a third median swelling derived from the 4th arch mesoderm innervation remains nerve of the 4th arch - Superior Laryngeal N (X) C. Thyroid Diverticulum develops at the posterior point of the terminal sulcus in the tongue This area in the adult is called the foramen cecum endodermal cells begin to proliferate, differentiate, invaginate, and migrate down the neck They are also pulled downward as the neck as embryo in general elongates. as these endodermal cells descend, they remain connected to their origination by a thyroglossal duct The thyroglossal duct usually disappears. The foramen cecum of the tongue is usually the only remaining evidence of these embryologic events The thyroid diverticulum branches and becomes bilobed Does this standard embryological branching pattern remind you of lung buds that also branch from endoderm?

This differentiated thyroid cell forms the lateral lobes of the thyroid gland, its isthmus, and possibly the pyramidal lobe Endodermal cells differentiate into follicular cells that produce thyroxin, triiodothyronine If downward migratory signaling doesn't occur, the thyroid tissue remains in its original location. It underdoes differentiation and begins to produce its products. These lingual thyroids can block an infants airway at birth. In view of this migratory pathway during development, it should not be surprising that thyroid cells can be distributed anywhere between the tongue and the normal position of the thyroid gland. In its extreme form, the thyorgloassal duct persists throughout the neck. In its less serious form, thyroglossal cysts can persist anywhere along the pathway. These cells are secretory but their products are not well drained by the extensive venous channels of the typical thyroid (superior, middle and inferior thyroid vv); thus thyroid products accumulate and produce cysts that must be removed. To completely obliterate the remaining thyroid cells it may be necessary to remove the median portion of the hyoid bone since this bone is the result of fusion and ossification from the 2nd and 3rd arch cartilages and thyroid tissue can get trapped inside the bone.

II. Fates of the Lateral Outpouchings of Endoderm

A. First Pharyngeal Pouch is located posterior to the first branchial arch skeleton This diverticulum elongates into a tubotympanic recess lined with endoderm These endodermal cells from this outwardly growing pouch come into close proximity to the ectodermal in-pocketing known as the external auditory meatus. Endodermal cells from both the dorsal and ventral pocket are stretched out into this pharyngotympanic tube (Eustachian tube). The distal end of 1st endoderm pouch enlarges and ultimately becomes the middle ear cavity lined with mucosa that originated in the posterior pharynx region and is therefore innervated by CN IX. Note that the 1st arch skeletal elements are trapped in this area and undergo endochondrial ossification (malleus, incus). Note that the 1st arch mesoderm also remains anterior to this endodermal pouch. Thus this mesoderm forms the tensor tympani muscle. Where the inwardly proliferating ectoderm approaches the outwardly proliferating endodermal pouch, a wafer thin mesoderm gets trapped thus the tympanic membrane (eardrum) is a rare spot where 3 germ layers are sandwiched together. B. Second Pharyngeal Pouch This one will be your favorite to remember The endoderm in this pouch doesnt apparently proliferation or migrate or get stretched out. This endoderm remains as a pouch and is known as the palatine fossa. It seems likely that these endodermal cells elaborate some homing signals and cell surface receptors such that lymphocytes secondarily invade this depression and reside here as The palatine Tonsil. This invasion of the pouch and proliferative of lymphocytes continues after birth and typically continues until 6 yrs of age when the tonsil reaches its maximum size and then usually regresses. C. Third Pharyngeal Pouch This endodermal diverticulum branches into a ventral and dorsal wing. Once again you see an endodermal branching pattern that is induced by select growth factors.

Ventrally positioned endodermal cells leave the central visceral tube and migrate downward and/or are stretched downward during neck formation. These cells are destined to differentiate into the thymus gland. The growth of the thymic material continues until adolescence then the gland undergoes involution and becomes fatty in the adult. Dorsally positioned endodermal cells from this lateral pharyngeal remain attached to their migrating ventral "cousins" for a time. For this reason, they are pulled downward but they still ultimately differentiate into Inferior parathyroid glands. Parathyroid nests can cease migration early and become incorporated into the dorsal surface of the nearby thyroid gland or They can fail to detach from their ventral cousins: and get pulled anywhere in the anterior mediastinum! This is a favorable circumstance if your patient requires a thyroidectomy and the surgeon does not wish to accidentally remove parathyroid glands. This is a somewhat troublesome circumstance if you have a patient who has diseased parathyroids that require removal. In this circumstance special tracers must be introduced to highlight the parathyroid material since it can be found anywhere in the anterior neck to mediastinum and there can be supernummary parathyroid nests as well.

D. Fourth Pharyngeal Pouch This diverticulum of endoderm also branches into a ventral and dorsal wing. Ventral cells are called the ultimobranchial body and become incorporated into the parathyroid cells in the thyroid interstium. Dorsal cells are not pulled downward by any connections (such as the migrating thymus gland) so they form the SUPERIOR parathyroid glands typically located on the dorsal surface of the thyroid gland. E. Clinical Problems - Branchial Cysts - Lateral Cysts Pediatricians occasionally notice patients with cysts or tiny oozing openings that are located in the skin anterior to the border of the stermomastoid muscle. These are known as branchial cysts or fistulas that are lined with endodermal (mucosal secretory) cells. These are akin to "gill slits" These trapped endodermal cells can drain externally or internally and they require surgical removal of all the remaining cells. During normal neck development in humans the 2nd arch mesoderm and ectoderm grows far more than the more caudal arches. This block of tissuei extends over the other arches like an operculum over the gills in bony fish. The cells lining this very normal cervical sinus can persist and begin to secrete These endodermal tracts of cells will can connect internally at either the 2nd or 3rd pouch or connect to the external surface anterior to the sternocleidomastoid muscle. In your surgical removal if this is the persistence of 2nd pouch, it will dump into the central visceral tube at the level of the tonsils. In your surgical removal if this is the persistence of the 3rd pouch, it will dump posterior to the 3rd arch derivatives and will therefore dump into the central visceral tube by piercing through the thyrohyoid membrane.

III. Development of the Eye

A. Initial Events The first visible evidence of eye formation appears at day 22 in the embryo.

The neuroectoderm becomes grooved on either side of the developing forebrain (neural tube). This neuroectoderm in this region are called the optic vesicles; they grow outward toward the surface ectoderm. This traps mesoderm between the surface and the brain and this material will develop into the associated blood supply. The surface ectoderm begins to get signals (is induced) to develop into a lens placode.

B. Further Differentiation from the Neuroectoderm & Cells which behave as though they are neural crest cells. As the optic vesicle continues to invaginate and grow outward from the diencephalon of the brain vesicle, it forms a double layered optic cup. The optic cup is a goblet shaped structure that elongates and leaves behind a connection to the developing brain. This is the optic stalk that will become the template for the optic nerve when the ganglion cells of the retina grow back centrally to hook up with their connections along the visual neuronal pathway. The optic cup has a deep fissure on its inferior surface. This is the choroid fissure and this groove allows for blood vessels to nourish the developing eye. The outer layer of the optic cup will form the melanin-containing pigmented layer of the retina. The inner layer of the optic cup will form the multiple neuronal layers of the retina. The nerve fibers of the ganglion layer will converge toward the optic stalk with gradually developing into the optic nerve. The small space between the inner and outer layers of the optic cup is eventually obliterated; however the layers never have a tight attachment. This is the anatomical reason why in adults the retina easily detaches from the pigmented layer. (From my perspective this seems like a design flaw). C. Further Differentiation of the Mesoderm and Mesenchyme that develops from Neural Crest origin At the posterior portion of the developing optic stalk and optic cup, an inward groove the choroid fissure becomes filled with mesoderm. This is how the blood supply gains interior access to the developing eye. This tissue develops into the hyaloid artery and hyaloid vein. These vessels sink into the choroids fissure which begins to overgrow and the hyaloid artery and vein appear to become incorporated into the optic stalk. The hyaloid vessels persist at their most posterior portions as the central artery and vein in the adult. Most anteriorly, the vessels typically obliterate but do occasionally persist in the vitrous humor where they interfere with the light pathway. The mesenchyme from neural crest origin appears to form the choroid layer, the sclera and its splits to form the anterior chamber. D. The Surface Ectoderm Meanwhile as the optic vesicle comes into close proximity to the surface ectoderm it thickens and eventually invaginates. The lens vesicle becomes detached from the surface and sinks inward. The lens vesicle cells begin to differentiate further and will develop into a lens At the surface the ectoderm further differentiates to form the cornea and the conjunctiva. I am deliberately refraining from discussing the other structures in the eye (iris, ciliary body, processes, sphincter and dilator) since this is a hot area of research that is changing as cell lineages tracing studies are rapidly changing established dogma. Most of the other structures appear at this point to come from the neural crest mesoderm that invades the head region.

E. Clinical Problems of Eye Development Coloboma when used as a general term this describes the congenital absence of tissue associated with the eye. Iris coloboma If the choroids fissure fails to close during the 7th week of development a cleft persists. Such a cleft is seen as a defect in the inferior portion of the iris. The spectrum of colobomal defects is broad. In its more serious form, the fissure can extend backward where there are 35% or 50% or greater defects in the retina itself. Persistent Iridopupillary membrane During the proliferation of the anterior-most mesenchymal cells in the eye region, some come to form a temporary layer (membrane) between the sinking lens vesicle and the surface ectoderm. Sometimes this tissue fails to completely obliterate and a highly fenestrated membrane is seen over the papillary area. This is its mildest form does not seem to significantly interfere with the light pathway to the retina.