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

Abstract

Mice that carry a mutation at the hairless (hr) locus develop seemingly normal hair follicles (HF) but shed their hairs completely soon after birth. Histologically , their HFs degenerate into characteristic utriculi and dermal cysts shortly after the entry of the HF into the first regression phase (catagen) , during the initiation of HF cycling. Here , we show that at least nine distinct stages of HF disintegration can be distinguished in hr/hr mice. Toward the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr skin undergoes premature and massive apoptosis. This is associated with a dyscoordination of cell proliferation in defined HF compartments, malpositioning of the proximal inner root sheath, striking atrophy of outer root sheath , and failure of trichilemmal keratinization in the developing club hair. Rather than undergoing their normal catagenassociated involution , the hair bulb and central outer root sheath disintegrate into separate cell clusters, thus disrupting all epithelial contact with the dermal papilla. Dermal papilla fibroblasts fail to migrate upward , and break up into clusters of shrunken cells stranded in the reticular dermis as dermal cyst precursors , while the upper HF epithelium transforms into utriculi. Some dermal papilla cells , which normally never undergo apoptosis , also become TUNEL؉ in hr/hr skin , and their normally high expression of a key adhesion molecule , neural cell adhesion molecule , declines. Thus , loss of a functional hr gene product (a putative zinc finger transcription factor) initiates a premature , highly dysregulated catagen, which results in the destruction of the normal HF architecture and abrogates the HF's ability to cycle. This provides new insights into the pathobiology of the hr mutation , and suggests that the normal hr gene product is a crucial element of catagen control. (Am J Pathol 1999, 155:159 -171)

(Neuro-)endocrinology of epithelial hair follicle stem cells

“…Despite otherwise complete HF destruction after the first entry into catagen, mutant mice with functionally defective hairless protein seem to retain a residual HFeSC pool (Panteleyev et al, 1999;Panteleyev et al, 2000a;Panteleyev et al, 2000b). Likewise, even in the absence of functional VDR HFs develop, and a HFeSC niche establishes itself.…”

“…In mice and man, VDR-mediated signaling is essential for normal HF development, growth, and cycling, and VDR mutations result in alopecia. The product of the hairless gene -a zinc finger protein like VDR, whose mutation, by itself, produces a very similar hair phenotype in mice and man as VDR mutants -serves as a nuclear co-repressor for VDR (Bergman et al, 2005; Bikle et al, 2006;Miller et al, 2001;.Despite otherwise complete HF destruction after the first entry into catagen, mutant mice with functionally defective hairless protein seem to retain a residual HFeSC pool (Panteleyev et al, 1999;Panteleyev et al, 2000a;Panteleyev et al, 2000b). Likewise, even in the absence of functional VDR HFs develop, and a HFeSC niche establishes itself.…”

The hairless (hr) gene is involved in the congenital hypotrichosis of Valle del Belice sheep

“…This gene is highly expressed in the brain and skin [1,4]. In its absence, hair follicles disintegrate and new hair is not induced [12]. Cachon-Gonzalez et al [4] described the gene expression in mice, and amplified the entire cDNA of the gene, which consists of 19 exons with a coding sequence of 3750 nucleotides.…”

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

“…1,2 Studies of genetically engineered and mutant mice with hair growth abnormalities have provided some insights into the molecular control of HF cycling. [3][4][5][6][7] At the same time, molecular genetic data alone are not sufficient for a complete understanding of the mechanistic role of regulatory molecules in HF neogenesis and remodeling, because the immediate cellular targets of these molecules remain unknown.…”

“…6 This gene is the target of several allelic mutations in laboratory rodents, [11][12][13] humans, 14 -16 and monkeys. 17 The attenuation of hairless gene activity in hr/hr mutants results in the progressive shedding of the infantile hairs in animals, which represents an analog of the autosomal recessive disorder papular atrichia (MIM 209500) in humans.…”