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Mouse models of alopecia: identifying structural genes that are baldly needed
Xuemei Tong1 and Pierre A. Coulombe2
1 2

Dept of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA Depts of Biological Chemistry and Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

The mature hair follicle undergoes a unique developmental cycle, in which phases of growth are interspersed with phases of involution and rest. The main effectors of this cycle are skin epithelial stem cells that reside in a specialized compartment of the follicle. Defects in this cycle, or in the structure of the hair produced, often result in alopecia (partial or complete hair loss), a condition that affects a signicant fraction of the population. Here we discuss transgenic mouse models that exhibit alopecia as a primary phenotype, resulting from the inactivation of genes encoding structural proteins. The various types of hair present in mammalian skin undergo a unique cycle throughout their existence, with phases of growth (ANAGEN ) (see Glossary) interspersed with phases of regression (CATAGEN ) and rest (TELOGEN ) (Fig. 1a) [1]. This cycle recapitulates several aspects of hair morphogenesis, a process initiated during embryonic development, and requires the integration of multiple stimulatory and inhibitory signals [2 5]. The mature pilosebaceous unit (Fig. 1b) is composed of a hair follicle, a sebaceous gland and smooth muscle, and can adjust the type of hair it produces in response to endocrine signals, such as those arising during puberty. Interestingly, the epithelial STEM CELL reservoir in adult hairy skin is probably located in a specialized region of the hair follicle, known as the BULGE . In addition to adult hair-follicle cycling, these epithelial stem cells participate in the renewal of epidermis, including the homeostatic response to skin injury, and are the likely source of many skin cancers. Premature hair loss, or that which accompanies certain drug regimens, is a perceived problem that affects a signicant proportion of the population, and is the basis of a multibillion dollar industry. Hence, there are medically compelling reasons for understanding the fundamentals of hair biology. The complex molecular events that control the formation of new follicles, and the re-entry of resting mature follicles into anagen, are now being dened and understood [3,4,6]. Recently, GENE INACTIVATION in laboratory mice has become an important tool in studying the role of various classes of proteins that are found in mammalian hair. Conveniently, in mice, the progression of individual follicles through the rst two iterations of the hair cycle
Corresponding author: Pierre A. Coulombe (coulombe@jhmi.edu).

occurs in a synchronized and spatially dened manner over a period of a few weeks [1]. Moreover, the mouse genome is amenable to the targeting of specic genes by homologous recombination, partly because of the availability of totipotent embryonic stem cells [7]. This gene knockout approach is the most denitive means of assessing the functional contribution of a gene product
Glossary
Acantholysis: Separation of keratinocytes from one another within the spinous layer of epidermis and in related stratied squamous epithelia. It frequently results from defects in cell cell adhesion. Anagen: Growth stage of the adult hair cycle. Apoptosis: Programmed cell death (signaled by the nucleus) in normally functioning cells when conditions dictate. It is an active process requiring metabolic activity by the dying cell, and is often characterized by cleavage of the DNA in a specic pattern. Cells dying by apoptosis do not usually elicit the inammatory responses that are associated with necrosis. Appendage: A structure arising from the surface, or extending beyond the tip, of another structure. Hair, nail and glands are collectively referred to as epithelial appendages in mammalian skin. Bulge: Local thickening of the epithelium of the outer root sheath at or near the point on insertion of the arrector pili muscle. The bulge is believed to house the epithelial stem cells in hairy skin. Catagen: Relatively short phase of the hair cycle during which the hair bulb (responsible for the production of the hair shaft) regresses, through carefully orchestrated epithelial apoptosis. Club hair sheath: The fully regressed bulb region in a resting (telogen-stage) hair. Consists of a bilayered epithelium onto which the base of the hair shaft is afxed. Co-allelic: A situation in which independent instances of similar phenotypes genetically map to the same allele (an allele is one of several alternative forms of a gene occupying a given locus on a chromosome). Dermal papilla: Knob-like indentation of the bottom of the hair follicle, upon which the hair bulb ts like a cap. It contains specialized broblasts with essential inductive properties that direct epithelial cells to produce hair tissue. It also contains vascular loops for the nourishment of hair tissue. Desmosome: Specialized cell cell junction into which intermediate laments are inserted. Desmosomes are particularly abundant in tissues that have to withstand mechanical stress, such as skin epithelium, muscle and endothelium. Ectoderm: The outer of the three germ layers of the embryo (the other two being mesoderm and endoderm). Ectoderm gives rise to epidermis and neural tissue. Exogen: Phase of the hair cycle during which the hair is actively being shed from its follicular sleeve. Gene inactivation: The generation of a mutant organism in which the function of a particular gene has been completely eliminated (a null allele). Also known as gene knockout. Hair bulb: The lower expanded extremity of the hair follicle that ts like a cap over the dermal papilla. Stem cell: Precursor cell that gives rise to a lineage of cells. This term is often used to describe the most primitive cells in a tissue setting, from which all the differentiated cell types are derived. Telogen: Resting phase of the adult hair cycle, during which no bulb or hairshaft tissue is being produced. Vibrissae: Stiff hairs projecting from the face around the nose of most mammals, acting as touch receptors.

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(a) Development
Integrin 1

(b)

Epidermis

Anagen
Keratin 17 Integrin 6 Whn Hoxc13

SG

APM Bulge Hair shaft IRS ORS Matrix Bulb

Telogen

Desmoglein 3

in a particular setting. The inactivation of genes encoding proteins that are crucial to the structure of the hair, or to the completion of its cycle, often causes alopecia. In this review, we focus on transgenic mouse models in which alopecia is a primary component of the phenotype following the inactivation of a gene encoding a structural protein, such as a cytoskeletal element, an adhesion molecule or a protease (Table 1). These models have received less attention than those involving alterations in effectors of key signaling pathways that operate in hairfollicle tissue [3,4,8]. The hair follicle and its growth cycle All epithelial APPENDAGES , including hair, nail, glands and teeth, develop from the single-layered ECTODERM during embryogenesis [1]. A mature hair follicle comprises seven distinct epithelial layers, each the product of a terminal differentiation pathway. These layers are organized in concentric circles around the main axis of the hair. From the inside out, they are the medulla, the cortex, and the cuticle (which form the hair shaft), another cuticle, Huxleys layer and Henles layer [which form the inner root sheath (IRS)], and the outer root sheath (ORS), an epithelium that wraps around the follicle and is contiguous with the

? Cathepsin L Catagen DP
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Fig. 1. Hair-follicle histology and growth cycle. (a) The hair cycle, in which phases of growth (anagen) are interspersed with phases of regression (catagen) and rest (telogen). The phases of the cycle affected by null alleles of particular genes are identied. (b) The major histological compartments that make up a pilosebaceous unit, as it would appear in an ideal cross-section through skin tissue. The dashed line depicts the position of the club hair sheath (the fully regressed bulb region) in the telogen stage. Abbreviations: APM, arrector pili muscle; DP, dermal papilla; IRS, inner root sheath; ORS, outer root sheath; SG, sebaceous gland.

Table 1. Mouse models of alopecia, with emphasis on genes encoding structural proteins
Gene knockout Keratin 17 Primary function Cytoskeleton Onset of alopecia Failure to grow a fur coat in the rst week post-birth; normalization starting at , 3 weeks of age Starting at , 3 weeks after birth; hair loss is short-lived but cyclical Starting at , 3 weeks after birth; hair loss is short-lived but cyclical; postnatal emergence of vibrissae is delayed Starting at , 5 days post-birth; normalization starting at , 20 30 days post-birth Affected areas Pelage hair over a signicant fraction of the body; occasionally, vibrissae Hair loss is cyclical and temporally patterned along the cephalocaudal axis Hair loss begins at the top of head and proceeds posteriorly Histological features Shorter hair length; hair fragility; degeneration within ORS, IRS, matrix; melanin pigment aggregates Telogen-phaseSpecic detachment of hair from the base of the follicle Delayed hair follicle morpho-genesis; Periodic loss and regrowth of hair Cellular mechanism Hair shaft fragility; apoptosis in matrix Recovery Yes Related human disease Pachyonychia congenita (type 2) Steatocystoma multiplex [16] Pemphigus vulgaris [18] Additional comments The phenotype is strain-dependent and does not mimic that associated with missense alleles in humans The Dsg3-null allele is co-allelic with the balding mutation locus The Ctsl-null allele is co-allelic with the furless mutation locus

Desmoglein 3 (Dsg3)

Cellcell adhesion

Defects in cellcell adhesion within the club hair sheath Possibly, alterations in the balance between proliferation and differentiation of progenitor epithelia cells in epidermis Persistent mononuclear cell inltrate

Cyclical

Cathepsin L (Ctsl)

Lysosomal cysteine proteinase of the papain family

Cyclical

Unknown

Integrin b6

Cell-matrix adhesion

Hair loss is restricted to areas of frequent trauma (e.g. dorsal aspect of head/neck, inner thigh surfaces)

Fewer follicular proles; Degeneration of follicles with focal mononuclear cell inltration Hair follicles are shorter, show an aberrant morphology, and exhibit reduced proliferation Hair breakage within the hair canal

Partial

Unknown

Integrin b1

Cell-matrix adhesion

From , 9 days after birth

All pelage hairs are affected

Whn (nude)

Transcription factor

No emergence of a fur coat during the rst week post-birth

All pelage hair; vibrissae are reduced in number and abnormal in shape

Reduced proliferation of matrix cells and defects in the organization of hairfollicle compartments Whn regulates the expression of hairdifferentiation genes

No

Unknown

Lungs are also signicantly affected; the anticipated healing defect was not observed in skin tissue. Signicant alterations in the basal lamina at the dermo epidermal junction, but not around hair follicles Mice show defects in epidermis, nail and thymus (leading to severe immunodeciency) Mice show defects in other appendages, incl. nail and liform papillae of the tongue

No

Alopecia with immunodeciency [38]

Hoxc13

Transcription factor

No emergence of a fur coat during the rst week post-birth

Absence of all pelage hair, peri-anal hair, cilia and vibrissae

Hair breakage within the hair canal (near the skin surface)

Hoxc13 regulates the expression of hairdifferentiation genes

No

Unknown

Abbreviations: IRS, inner root sheath; ORS, outer root sheath.

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(a)

(b)

(c)

MPA

DP

DP

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Fig. 2. Mice null for the gene encoding keratin 17 exhibit age- and strain-dependent alopecia. (a) The phenotypic appearance of a 14-day old mouse null for the gene encoding keratin 17 (K17 2/2 ) in the C57Bl/6-strain background (right) compared with that of a wild-type littermate (K17 / ) (left). (b,c) Hematoxylin and eosin staining of sections prepared from parafn-embedded back skin. (b) The hair-bulb region from a 10-day old K17 2/2 mouse shows destruction of hair tissue via apoptosis (seen here as pycnotic nuclei within the boxed area), and the formation of large melanin pigment aggregates (MPA). In addition to apoptosis, hair fragility contributes to hair loss in K17 2/2 mice. (c) The hair bulb from a K17 /2 littermate, which shows a normal phenotype. DP, dermal papilla. Scale bars in (b) and (c) represent 100 mm.

epidermis (Fig. 1b). This basic histological blueprint is largely conserved among the various types of hair follicles that are present in mammals [1,9]. Hair-follicle morphology changes dramatically as the tissue progresses through its growth cycle in mature skin. During anagen, the follicle extends deep into the dermis, terminating at an inverted-bell-shaped structure, called the DERMAL PAPILLA , which houses a pocket of specialized broblasts. Directly above the papilla, separated by a thin basal lamina, is the matrix, a group of rapidly dividing epithelial cells that are progenitors for the hair shaft and IRS compartments (Fig. 1b). The broblasts of the dermal papilla possess essential inductive properties that both direct an appendageal fate within the embryonic ectoderm during development, and stimulate the sustained proliferation of matrix epithelial cells in the anagen-stage, mature follicle. At the conclusion of the anagen stage, the lower portion of the follicle undergoes catagen, a carefully orchestrated destruction by APOPTOSIS . The dermal papilla is spared during this process, and migrates upwards with the regressing catagen follicle. The resulting telogen hair is a quiescent tissue in terms of mitotic activity. It is likely that shedding of the hair represents a distinct step in the cycle, known as EXOGEN [10]. Reactivation of the anagen stage is believed to occur as a result of the exposure of the epithelial stem cells of the bulge (Fig. 1b) to cues emanating from the activated dermal papilla [11]; subsequent proliferation of bulge-derived progenitor cells produces a new HAIR BULB with a functional matrix. The main determinants of the width and length of the hair are the size of the dermal papilla and the time spent in the anagen phase of the cycle, respectively. In
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addition to reciprocal interactions involving the dermal papilla and either the bulge or the matrix, it is likely that interactions between other compartments of the hair follicles are required during the hair growth cycle. More detailed accounts of this subject can be found in Refs [1 4,8]. Transgenic mouse models of alopecia Keratin 17 Of the , 50 keratin genes present in mammalian genomes, more than half are expressed in at least one of the epithelial compartments that make up the hair follicle. As a result, analyses of keratin gene regulation are useful in monitoring differentiation within the pilosebaceous unit and other complex epithelia. The expression of so many related genes is typically associated with functional redundancy, but nullication of the gene encoding type-I keratin 17 (K17), which is expressed throughout the ORS, and in the matrix and medulla of the mature hair follicle, causes a signicant delay in the postnatal emergence of fur, owing to a combination of hair fragility and apoptosis of matrix epithelial cells (Fig. 2 and Table 1) [12]. The epithelial fragility observed in K17-null mice was expected, because keratin laments contribute to protecting epithelial cells against various forms of stress [13]. However, the apparent role of K17 in promoting the survival of matrix epithelial cells (Fig. 2) was not anticipated, but is lent credence by the earlier discovery of a similar role for the K8 K18 pair in hepatocytes [14,15]. Although severe, the alopecia seen in K17-null mice lasts only for a short period, and normalizes following the rst postnatal anagen, which occurs approximately three weeks after birth. The phenotype also shows a

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marked strain dependence. Both the brevity and the strain dependence correlate with a compensatory induction of K16, a keratin related to K17 [12]. The K17-null phenotype differs in many respects from the clinical presentation of patients harboring missense K17 alleles. These individuals develop one of two conditions, both related to ectodermal dysplasias, known as pachyonychia congenita and steatocystoma multiplex, which primarily affect nail and sebaceous gland, respectively, although other epithelial appendages (including hair) are also affected [16]. The epithelial lesions observed in these patients are atypical of keratin-gene disorders and, hence, it is worth testing whether they correspond to gain-offunction phenotypes. Adhesion molecules Cell cell and cell matrix adhesion complexes are abundant within skin epithelia. They show great variety, and some of their key constituents are encoded by multigene families. Interesting alopecia phenotypes have been reported in mice carrying null alleles for the genes encoding desmoglein 3 (Dsg3), integrin b6 and integrin b1 (Table 1). Desmogleins (Dsg1 3) and desmocollins (Dsc1 3) are transmembrane glycoproteins of the cadherin superfamily that are responsible for adhesive interactions between neighboring cells engaged in a DESMOSOME cell cell contact [17]. The basal and rst suprabasal layers of epidermis are enriched with Dsg3. Circulating auto-antibodies directed against Dsg3 underlie the pathogenesis of the oral and skin epithelial blisters seen in patients with pemphigus vulgaris (PV) [18]. Mice carrying a null mutation at the Dsg3 locus develop PV-like lesions, in which the function of Dsg3-containing desmosomes is impaired, leading to ACANTHOLYSIS and blister formation. Furthermore, lesions in the oral mucosa lead to reduced food intake, poor growth (runting) and, in some cases, death within 3 4 weeks after birth [19]. The surviving null mice show cyclical alopecia, beginning at approximately three weeks after birth [19,20]. The hair of Dsg3-null mice is prematurely shed at the telogen stage of the hair cycle, owing to defects in the desmosomes that are normally responsible for the integrity of the CLUB HAIR SHEATH , a bilayered epithelium that secures the hair at the base of the resting follicle. The runting and hair loss exhibited by these mice are identical to those of a spontaneous mutant mouse strain, known as balding, which is CO-ALLELIC with the Dsg3 locus [19,20]. Unlike other aspects of the Dsg3-null phenotype, the cyclical alopecia cannot be compensated for by other desmogleins (e.g. Dsg1). Although keratin laments are attached to desmosomes, and both K17 and Dsg3 are expressed in the club hair sheath [20,21], the available data suggest that distinct mechanisms are involved in the hair loss that occurs in K17-null and Dsg3-null mice (Table 1). Epithelial cells depend on complex interactions with the extracellular matrix for attachment, and also for the interpretation of outside signals that control fundamental activities, such as migration and the balance between growth and differentiation. A large family of integrin transmembrane receptors is involved in these
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interactions. Integrins form heterodimers that are composed of an a subunit, which denes the extracellular ligand specicity, and a b subunit, which interacts with intracellular signaling molecules and with the cytoskeleton [22]. Integrin b1 is prominent in the basal layer of epidermis and hair-follicle epithelia, where it pairs with a2, a3, and a5 to form surface receptors for collagen, laminin-5 and bronectin, respectively. Interestingly, epithelial stem cells of the skin are believed to exhibit higher levels of integrin b1 [23]. Conventional targeting and inactivation of the b1 locus leads to early embryo lethality, reecting the fundamental role of this integrin in developing tissues [24,25]. If the gene inactivation event is restricted to the basal layer of stratied squamous epithelia (i.e. a conditional knockout), the resulting mice survive beyond birth but exhibit an interesting epithelial phenotype: developing hair germs fail to complete their downward migration into the dermis, and do not undergo the differentiation events that produce the various epithelial compartments that make up a follicle [26,27]. Moreover, matrix cells exhibit reduced mitotic activity in conditional b1-null mice. These studies suggest that integrin b1 has important roles in proliferation (although not in survival) of matrix cells, and in the formation of the compartmental organization of the follicle. Mice null for the gene encoding b6 integrin exhibit a milder phenotype, with alopecia restricted to areas of frequent frictional trauma, such as the head and neck area, and the inner thighs [28]. The mechanism(s) leading to this hairlessness are extrinsic to the epithelium, and the histology of b6-null skin reveals prominent mononuclear inltrates, including macrophages, at sites of alopecia. By contrast with b1, the b6 subunit pairs exclusively with aV to form a receptor for bronectin on the surface of basal epithelial cells. Hence, it is possible that the aVb6 receptor normally restricts the trafcking of mononuclear cells to skin epithelia [28]. These ndings are consistent with the notion that hairtissue function is sensitive to cues emanating from inammatory and immune effectors [29]. Hair loss is also seen in mice carrying a null allele for the gene encoding integrin b2 [30], but in this instance it is late in onset and progressive, and appears to result from general epithelial alterations associated with severe dermatitis. A similar phenotype characterizes Dsc1-null mice, which exhibit multiple epithelial aberrations prior to the onset of localized hair loss starting at six weeks of age [31]. Conditional gene disruptions restricted to hair follicles would provide more specic information about the role of these molecules in hair tissue. Cathepsin L Of all the genes discussed in this review, the one encoding cathepsin L (Ctsl) (Table 1), a lysosomal cysteine protease of the papain family, is probably the least expected. Mice homozygous for a null Ctsl allele do not show VIBRISSAE at birth and exhibit periodic hair loss with timing that is characteristic of a haircycle-specic defect [32]. In these mice, the epidermis and hair matrix are hyperproliferative and acanthotic,

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and the hair follicles exhibit dilated hair canals and disturbed club hair formation. Ex vivo culture studies suggest that the defects are intrinsic to the skin epithelium, despite the ubiquitous distribution of this protease. It is thought that the transition between the catagen and telogen phases of the hair cycle is delayed and aberrant in Ctsl-null mice [32]. This mutation has also been shown to be co-allelic with the furless mutation, which arose spontaneously more than 40 years ago [33]. It is surprising that a protease thought to be conned to lysosomes plays a crucial role in hair biology; the absence of this enzyme might affect the hair cycle through an impact on the balance between proliferation and differentiation in skin epithelia [32]. The substrates whose altered processing accounts for the hair-loss phenotype in the Ctsl-null and furless mice have yet to be identied. Whn and Hoxc13 transcription factors Several mouse models have been produced in which disruption of a gene encoding a signaling molecule or transcription factor has resulted in a hair-loss or hairalteration phenotype (for recent reviews see [3,4,8]). Among these, two models are particularly relevant because the alopecia phenotype they exhibit results, at least in part, from reduced expression of structural genes in hard epithelia. These two models are nude (Whn-null) and Hoxc13-null mice (Table 1). The nude strain arose spontaneously, and shows defects in the keratinization of the hair shaft and in the differentiation of epithelial progenitor cells in the thymus [34]. The product of the Whn locus is a member of the forkhead/winged helix family of transcription factors, and is actively expressed in the anagen, but not telogen, phase of the hair cycle [35]. The Hox gene family contributes signicantly to antero posterior patterning during much of embryogenesis. The expression of Hoxc13 occurs relatively late in embryogenesis, and is restricted to specic compartments within epithelial appendages, including hair follicles [36]. In both Whn-null and Hoxc13-null mice, hair follicles do form but they produce an abnormal hair that is brittle and, as a result, fractures readily within the hair canal. Both Whn and Hoxc13 have recently been shown to inuence the transcriptional regulation of hard keratin genes [35,37]. Mutation of the Whn gene causes severe immunodeciency, in addition to alopecia [38]. These mouse models provide a unique opportunity to identify (e.g. through genomics and proteomics) structural genes whose products are crucial to the process of making a hair. Conclusions For many of the mouse models discussed here, the relationship between genotype (the null allele) and phenotype (alopecia as a primary characteristic) could not have been predicted from the regulation of the gene involved or from the properties of its product. Hence, in addition to information about the functional properties of specic proteins, studies of mouse models of alopecia provide novel insight into the workings of hair-follicle tissue [5]. In some cases, such as nude (Table 1) and hairless mice, mouse models can also act
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as a predictor of the faulty gene in human subjects suffering from a phenotypically similar condition [38,39], and are therefore potentially useful for testing novel, disorder-specic experimental strategies. There are many spontaneous-mutant mouse models in which a single gene defect gives rise to alopecia associated with physical alterations in differentiated structure(s) within the hair follicle (reviewed in [40]). Forward- and reverse-genetics strategies carried out in mice will continue to enhance our understanding of hair-follicle tissue, and might suggest new avenues for the therapeutic management of alopecia and other hair-tissuerelated conditions.
Acknowledgements
Work in our laboratory is supported by grants AR42047 and AR44232 from the National Institute of Musculoskeletal, Arthritis and Skin Diseases.

References
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20 Koch, P.J. et al. (1998) Desmoglein 3 anchors telogen hair in the follicle. J. Cell Sci. 111, 2529 2537 21 Bernot, K. et al. (2002) Keratin 16 expression denes a subset of epithelial cells during skin morphogenesis and the hair cycle. J. Invest. Dermatol. 119, 1137 1149 22 Martin, K.H. et al. (2002) Integrin connections map: to innity and beyond. Science 296, 1652 1653 23 Watt, F.M. (2002) Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 21, 3919 3926 24 Fassler, R. and Meyer, M. (1995) Consequences of lack of b1 integrin gene expression in mice. Genes Dev. 9, 1896 1908 25 Stephens, L.E. et al. (1995) Deletion of b1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev. 9, 1883 1895 26 Brakebusch, C. et al. (2000) Skin and hair follicle integrity is crucially dependent on b1 integrin expression on keratinocytes. EMBO J. 19, 3990 4003 27 Raghavan, S. et al. (2000) Conditional ablation of b1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J. Cell Biol. 150, 1149 1160 28 Huang, X.Z. et al. (1996) Inactivation of the integrin b6 subunit gene reveals a role of epithelial integrins in regulating inammation in the lung and skin. J. Cell Biol. 133, 921 928 29 Paus, R. et al. (1998) Generation and cyclic remodeling of the hair follicle immune system in mice. J. Invest. Dermatol. 111, 7 18 30 Bullard, D.C. et al. (1996) A polygenic mouse model of psoriasiform

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skin disease in CD18-decient mice. Proc. Natl. Acad. Sci. U. S. A. 93, 2116 2121 Chidgey, M. et al. (2001) Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation. J. Cell Biol. 155, 821 832 Roth, W. et al. (2000) Cathepsin L deciency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J. 14, 2075 2086 Green, E.L. (1954) The genetics of a new hair deciency, furless. J. Hered. 45, 115 118 Flanagan, S.P. (1966) Nude, a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8, 295 309 Schlake, T. et al. (2000) Forkhead/winged-helix transcription factor Whn regulates hair keratin gene expression: molecular analysis of the nude skin phenotype. Dev. Dyn. 217, 368 376 Godwin, A.R. and Capecchi, M.R. (1998) Hox13c mutant mice lack external hair. Genes Dev. 12, 11 20 Jave-Suarez, L.F. et al. (2002) HOXC13 is involved in the regulation of human hair keratin gene expression. J. Biol. Chem. 277, 3718 3726 Frank, J. et al. (1999) Exposing the human nude phenotype. Nature 398, 473 474 Ahmad, W. et al. (1998) Alopecia universalis associated with a mutation in the human hairless gene. Science 279, 720 724 Nakamura, M. et al. (2001) Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: annotated tables. Exp. Dermatol. 10, 369 390

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