Towards Defining the Pathogenesis of the Hairless Phenotype

Abstract

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.

The Role of the Hairless (hr) Gene in the. Regulation of Hair Follicle Catagen Transformation

“…21 Air-dried 6-m cryostat sections were collected on silane-coated slides, fixed in cold acetone (Ϫ20°C) for 10 minutes, and then processed for neural cell adhesion molecule (NCAM) 19,25 and interleukin-1 receptor type 1 (IL-1R1) 26 immunohistochemistry. Alkaline phosphatase (AP) activity was visualized according to the staining protocol routinely used in AP or APAAP immunohistochemistry, but without the customary blocking of endogenous AP by levamisole.…”

“…9,16 -18 Our previous study of the fully developed hairless phenotype in adult 3-to 4-month-old HRS/J hr/hr mice had suggested that the hr mutation disrupts the integrity of selected functional tissue units in most HF compartments, including the isthmus and hair bulb region as well as the dermal papilla. This prompted us to speculate that HF disintegration in hr/hr mice might result from a disturbance in apoptosis and/or an impairment of cell adhesion, 10,19 which remains to be demonstrated. Also, these studies did not address the earliest stages of hr phenotype development in neonatal hr/hr mice undergoing their first synchronized, spontaneous HF regression (catagen).…”

Patterns of Hairless (hr) Gene Expression in Mouse Hair Follicle Morphogenesis and Cycling

“…As we have shown previously, in hairless mouse skin the switch from anagen to catagen is associated with a dramatic and premature up-regulation of apoptosis in the HF matrix. 6 These observations, together with data on the discoordination of keratinocyte apoptosis and differentiation in epidermis and utricular epithelium of hairless mouse skin, 22,34 suggest that normal expression of the hr gene seems to regulate the balance between apoptosis and differentiation in selected HF keratinocyte populations.…”

“…The interfollicular epidermis and utricular epithelium in hairless HRS/J hr/hr mutant mice are characterized by excessive cornification. 22,33 This feature is associated with simultaneous up-regulation of both keratinocyte proliferation 22 and apoptosis, 34 suggesting an elevated rate of cell turnover in the epidermis and utricular epithelium of hairless mouse skin. Because hr is actively expressed in both of these cell populations (in normal interfollicular epidermis and in the HF infundibulum, which corresponds to the utricular epithelium), it might be implicated in the regulation of Figure 2.…”

“…18 Our recent studies on the successive pathomorphology of hairlessness have revealed that the attenuation of hr gene activity results in premature and excessive apoptosis and discoordination of cell death, proliferation, and adhesion in selected HF cell populations during the first transition from the anagen to the catagen phase of the HF cycle. 6,22 These functional and morphological studies were supported by recent progress in understanding molecular aspects of hr gene biology. 15,23 At the same time, however, some basic questions surrounding hr gene biology remain unanswered.…”