The Hedgehog and the hair follicle: a growing relationship

Andrzej Dlugosz

J Clin Invest. 1999;104(7):851-853. https://doi.org/10.1172/JCI8416.

Commentary

The various forms of hair loss (alopecia) constitute an extremely common complaint among both men and women. Although sometimes dismissed as merely cosmetic, these conditions can be psychologically and socially devastating. The desire to regrow hair is at the root of a multi-billion dollar industry worldwide; however, there are few truly effective treatments. Given the recent progress in elucidating some of the signals regulating hair follicle growth and development, there is hope that more useful therapies may soon be available. The timely report by Sato et al. (1) presents interesting new data bearing on this issue. The mature hair follicle is constructed of concentric layers of epithelial cells surrounding the hair shaft (Figure 1). The deepest portion of the follicle, the hair bulb, contains a mesenchymal dermal papilla enveloped by rapidly proliferating hair matrix cells. These epithelial cells give rise to 6 terminally differentiated cell types in the hair shaft and inner root sheath. Most hairs contain a medulla, cortex, and cuticle; external to this are the inner root sheath cuticle, and Huxley’s and Henle’s layers. The outer root sheath is continuous with the epidermis and sebaceous gland, and forms the outermost layer, extending down to and surrounding the hair follicle bulb. A specialized region of the outer root sheath called the “bulge,” located just beneath the sebaceous gland at […]

Find the latest version: https://jci.me/8416/pdf The Hedgehog and the hair follicle: Commentary a growing relationship See related article this issue, pages 855–864.

Andrzej Dlugosz Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 3310 CCGC/Box 0932, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0932, USA Phone: (734) 763-0355; Fax: (734) 763-4575; E-mail: [email protected]

The various forms of hair loss (alope- lineage determination, melanogene- The reactivation of follicle growth cia) constitute an extremely common sis, and the molecular regulation of with the onset of each anagen phase has complaint among both men and growth and development. led investigators to propose that some women. Although sometimes dis- Unlike other organs in the adult, the of the same signals that regulate follicle missed as merely cosmetic, these con- hair follicle is remarkably dynamic and formation during embryogenesis may ditions can be psychologically and continuously cycles through periods also operate in adult skin. The detailed socially devastating. The desire to of active growth (anagen), regression analysis of classical tissue recombinants regrow hair is at the root of a multi-bil- (catagen), and quiescence (telogen) (4) has revealed that the development of lion dollar industry worldwide; how- (Figure 1). The duration of anagen is hair follicles and feathers, like that of ever, there are few truly effective treat- an important determinant of hair other organs, is dependent on sequen- ments. Given the recent progress in length, and may thus be as long as 6 tial inductive interactions involving elucidating some of the signals regu- years for scalp follicles and as short as adjacent epithelial and mesenchymal lating hair follicle growth and devel- 6–8 weeks for eyebrow follicles (5). In cell populations (7). Indeed, embryonic opment, there is hope that more use- contrast to the complex anagen hair skin has served as an exceptionally use- ful therapies may soon be available. follicle, the telogen follicle is a diminu- ful experimental model for studying The timely report by Sato et al. (1) tive organ consisting of a sebaceous factors involved in patterning; the presents interesting new data bearing gland, a small number of quiescent establishment and maintenance of on this issue. outer root sheath cells surrounding polarity; growth; programmed cell The mature hair follicle is con- the base of the hair shaft, and dermal death; and terminal differentiation (8). structed of concentric layers of papilla cells lying adjacent to the As a foundation for understanding epithelial cells surrounding the hair remaining follicle epithelium. Activa- the molecular basis of hair follicle mor- shaft (Figure 1). The deepest portion tion of bulge keratinocytes in early phogenesis, the expression patterns of of the follicle, the hair bulb, contains anagen is believed to provide the tran- various genes involved in the develop- a mesenchymal dermal papilla sient amplifying cells needed to repop- ment of other embryonic structures enveloped by rapidly proliferating ulate the newly forming follicle (2, 3). have been examined in skin. These hair matrix cells. These epithelial cells Hair cycling thus involves the pro- genes encode members of the FGF, give rise to 6 terminally differentiated grammed destruction and reconstruc- TGF-β, WNT, Hedgehog, Notch, and other cell types in the hair shaft and inner tion of epithelial cells comprising the signaling pathways (reviewed in refs. root sheath. Most hairs contain a entire lower two thirds of the hair fol- 9–11). The appearance of new hair fol- medulla, cortex, and cuticle; external licle, including the hair matrix and licles in postnatal mouse skin express- to this are the inner root sheath cuti- inner root sheath. Unlike the follicle ing a truncated β-catenin mutant (12) cle, and Huxley’s and Henle’s layers. epithelium, the number of dermal suggested an important role for this The outer root sheath is continuous papilla cells remains relatively con- factor in the initiation of hair follicle with the epidermis and sebaceous stant throughout the hair cycle. This development, although these mice also gland, and forms the outermost layer, small cluster of mesenchymal cells went on to develop well-differentiated extending down to and surrounding possesses remarkable inductive poten- hair follicle tumors. the hair follicle bulb. A specialized tial, and may hold the key to under- Shh is one of a family of related lig- region of the outer root sheath called standing how hair follicle growth is ands involved in a remarkable variety of the “bulge,” located just beneath the regulated: implantation of dermal developmental processes, including the sebaceous gland at the insertion site papilla cells beneath naive epidermis establishment of left-right asymmetry, of the arrector pili muscle, contains results in de novo formation of mature neural tube and somite patterning, cells with stem cell properties (2, 3). hair follicles, even in skin that is nor- craniofacial and limb development, and Actively growing follicles also contain mally hairless (6). As most nonscarring the formation of several organs melanocytes that transfer pigment to alopecias can be attributed to abnor- (reviewed in refs. 13, 14). Shh produced matrix keratinocytes, imparting color malities involving the hair cycle, by one population of cells alters the to the developing hair. The follicle is understanding how this process is reg- developmental fate of neighboring tar- thus a rich model for studying epithe- ulated may yield important clues for get cells in a concentration-dependent lial-mesenchymal interactions, cell effective treatment. manner. According to the current

The Journal of Clinical Investigation | October 1999 | Volume 104 | Number 7 851 Figure 1 Hair follicle development and postnatal cycling. A series of epithelial and mesenchymal signals specify when and where primordial skin appendages, comprising an epithe- lial placode and dermal condensate, will appear. Addi- tional signals bring about the rapid growth and tissue remodeling that underlie formation of a mature hair fol- licle, with Shh playing a pivotal role in this process. New findings suggest that Shh is also capable of operating in adult skin, where it may be involved in triggering reentry into the active growth phase of the hair cycle, (anagen).

model, Shh interacts with and blocks quent stages of hair follicle develop- abnormalities in skin 6 months after the function of a cell-surface receptor ment was severely impaired in the skin injection argues against any deleteri- called Ptch1, which normally inhibits a of mutant animals. These studies ous long-term consequences. third protein called Smo (15). During revealed an essential function for Shh What is the specific target cell embryogenesis, Shh-mediated dere- as a fundamental growth regulator in responding to exogenous Shh in pression of Smo results in temporally embryonic hair follicles, and set the injected skin, and is this same cell type and spatially restricted activation of stage for future studies exploring the activated by Shh during the normal Shh target genes, which include the potential involvement of Shh in post- transition to anagen? Based on the transcription factor Gli1 and Ptch1 natal follicle function. nature of the technique used for their itself. The expression level of these tran- In this issue, Sato et al. demonstrate studies, it is not surprising that Shh scripts is thus a reliable indicator of that Shh, delivered by subcutaneous mRNA was detected in several differ- Shh pathway activity. Intense interest in injection of an adenoviral expression ent cell types scattered throughout the Shh signaling in skin was fueled by the vector, is capable of profoundly treated areas of skin (1). What is some- discovery that loss-of-function muta- affecting the hair cycle in postnatal what surprising is that the induction tions affecting the PTCH1 gene occur in mice (1). They propose that Shh acts of anagen was remarkably uniform in both familial and sporadic basal cell as a biologic switch that triggers telo- the injected areas despite the fact that carcinoma (16, 17), resulting in consti- gen hair follicles to enter anagen. Shh expression was mosaic. To help tutive Shh pathway activation. These investigators also demonstrate understand this result, it will be What is the normal function of Shh that spontaneous anagen is associat- important to identify the cells res- in skin? During development, Shh ed with transient upregulation of ponding directly to Shh by examining expression is restricted to the epithelial endogenous Shh and Ptch1 tran- the in situ expression of Shh target placode of primordial hair follicles, scripts, suggesting that activation of genes during the normal transition to whereas Ptch1 mRNA is detected in the Shh pathway may be the physio- anagen and in response to exogenous both the placode and dermal conden- logical signal stimulating follicle Shh. Even though the expression of sate (Figure 1) (18, 19). This expression growth. Although additional studies exogenous Shh may be widespread, pattern suggested a role for Shh sig- will be required to test this hypothe- responsiveness of specific cell types to naling in developing skin, and analysis sis, the data presented by Sato et al. Shh in the skin is likely to be tightly of Shh mutant mice revealed that this convincingly show that transient regulated both in space and time (22). molecule was required for hair follicle expression of a single key regulatory As there is strong evidence that dermal morphogenesis (20, 21). Although pla- molecule is sufficient to activate a papilla cells play a central role in regu- codes and dermal condensates were complex morphogenetic program in lating growth of the follicle epitheli- detected in both wild-type and Shh–/– postnatal rodent skin. Notably, the um, perhaps these are the critical tar- embryos, progression through subse- lack of any gross or histological get cells for Shh, and the observed

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