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A detailed characterization of the normal (in situ) human hair follicle cycle, supplemented with expressional data on specific hair follicle markers, has been awaited by basic hair researchers and dermatologists. Combining this hair cycle guide, together with a thorough analysis of the human-on-mouse hair xenograft model, provides solid ground for examining human hair cycle biology and pathology and for hair cycle-related pharmacological testing., (Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.)

The in vivo functions of the activin A receptor type 1b (Acvr1b) have been difficult to study because Acvr1b(-/-) mice die during embryogenesis. To investigate the roles of Acvr1b in the epithelial tissues, we created mice with a conditional disruption of Acvr1b (Acvr1b(flox/flox)) and crossed them with K14-Cre mice. Acvr1b(flox/flox); K14-Cre mice displayed various degrees of hairlessness at postnatal day 5, and the phenotype is exacerbated by age. Histological analyses showed that those hair follicles that developed during morphogenesis were later disrupted by delays in hair cycle reentry. Failure in cycling of the hair follicles and regrowth of the hair shaft and the inner root sheath resulted in subsequent severe hair loss. Apart from previous reports of other members of the transforming growth factor-β/activin/bone morphogenic protein pathways, we demonstrate a specialized role for Acvr1b in hair cycling in addition to hair follicle development. Acvr1b(flox/flox); K14-Cre mice also had a thicker epidermis than did wild-type mice, which resulted from persistent proliferation of skin epithelial cells; however, no tumor formation was observed by 18 months of age. Our analysis of this Acvr1b knockout mouse line provides direct genetic evidence that Acvr1b signaling is required for both hair follicle development and cycling.

We have examined the expression of the Hoxa4 gene in embryonic vibrissae and developing and cycling postnatal pelage hair follicles by digoxigenin-based in situ hybridization. Hoxa4 expression is first seen in E13.5 vibrissae throughout the follicle placode. From E15.5 to E18.5 its expression is restricted to Henle's layer of the inner root sheath. Postnatally, Hoxa4 expression is observed at all stages of developing pelage follicles, from P0 to P4. Sites of expression include both inner and outer root sheaths, matrix cells, and the interfollicular epidermis. Hoxa4 is not expressed in hair follicles after P4. Hoxb4, however, is expressed both in developing follicles at P2 and in catagen at P19, suggesting differential expression of these two paralogous genes in the hair follicle cycle.

Mutation of the hairless (hr) gene in mice causes severe abnormalities during the first hair follicle regression (catagen), resulting in complete baldness. Here, we further characterize how hairlessness develops in HRS/J hairless mouse skin (hr) by histology, histochemistry, immunohistology, and in situ hybridization. We show that, in hr skin, only two defined epithelial cell populations in the distal outer root sheath (ORS) retain their integrity, whereas the rest of the ORS disintegrates. The surviving distal ORS forms the characteristic utriculi, whereas the remnants of the bulge get isolated from other epithelial compartments, but retain the capacity to proliferate and to produce either columnar epithelial outgrowths or selected dermal cysts. Normal dermal papilla structures get lost during the development of hairlessness. Based on the patterns of keratin 17 mRNA and neural cell adhesion molecule antigen expression, and on the distribution of alkaline phosphatase activity, we propose that dermal cysts in hr skin arise from (i) the central ORS, (ii) bulge-derived cells, or (iii) the disintegrating proximal ORS under the influence of dermal papilla remnants. The hr mutation seems to disrupt the integrity of key functional tissue units in the hair follicle, possibly due to a dysregulation of normal, catagen-associated apoptosis and/or an impairment of cell adhesion, whereas the distal follicle epithelium (including its stem cell region) seems to be largely protected from this. Thus, hairless mice offer a unique model for dissecting the as yet obscure functional properties of the hr gene product in maintaining follicle integrity during normal catagen.

Keratin 17 (K17) expression is currently considered to be associated with hyperplastic or malignant growth of epithelial cells. The functions of this keratin in normal skin physiology and the regulation of its gene expression, however, are still unclear. As one possible approach to further explore K17 functions, we have studied the differential patterns of mouse K17 (MK17) transcription during the murine hair cycle by means of in situ hybridization, using a digoxigenin-labeled riboprobe. Cycling hair follicles in the skin of C57BL/6 mice were found to be the only skin structures expressing MK17 under physiologic conditions. MK17 transcripts were constantly observed throughout all hair cycle stages in the suprainfundibular outer root sheath (ORS). The MK17 expression was also evident in the isthmus part of the ORS, where it was expressed weakly and was spatially restricted during telogen, with an increase in early anagen and stable expression during mid- and late anagen, localizing to the zone of so-called trichilemmal keratinization. In addition, in early anagen, a group of epithelial cells in or next to the bulge region stained weakly for MK17. With progressing anagen development, MK17 expression in this region increased and was consistently localized to keratinocytes at the advancing front of the emerging epithelial hair bulb. In mid- and late anagen, this zone of MK17 expression spread along the proximal ORS, with a maximal level of expression in the innermost cell layer of the ORS. Overall, these findings provide data on the MK17 expression profile of normal murine skin and demonstrate hair-cycle-dependent regulation of MK17 expression.