The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation

Mice that carry a mutation at the hairless (hr) locus develop seemingly nor mal hair follicles (HF) but shed their hairs completely soon after birth. H istologically, their HFs degenerate into characteristic utriculi and dermal cysts shortly after the entry of the HF into the first regression phase (c atagen), during the initiation of HF cycling. Here, we show that at least n ine 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 assoc iated with a dyscoordination of cell proliferation in defined HF compartmen ts, malpositioning of the proximal inner root sheath, striking atrophy of o uter root sheath, and failure of trichilemmal keratinization in the develop ing club hair. Rather than undergoing their normal cartagen-associated invo lution, the hair bulb and. central outer root sheath disintegrate into sepa rate cell clusters, thus disrupting all epithelial contact with the dermal papilla, Dermal papilla fibroblasts fail to migrate upward, and break up in to clusters of shrunken cells stranded in the reticular dermis as dermal cy st 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 function al 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 sugges ts that the normal hr gene product is a crucial element of catagen control.