Hairless is a nuclear receptor corepressor essential for skin function

Abstract

The activity of nuclear receptors is modulated by numerous coregulatory factors. Corepressors can either mediate the ability of nuclear receptors to repress transcription, or can inhibit transactivation by nuclear receptors. As we learn more about the mechanisms of transcriptional repression, the importance of repression by nuclear receptors in development and disease has become clear. The protein encoded by the mammalian Hairless (Hr) gene was shown to be a corepressor by virtue of its functional similarity to the well-established corepressors N-CoR and SMRT. Mutation of the Hr gene results in congenital hair loss in both mice and men. Investigation of Hairless function both in vitro and in mouse models in vivo has revealed a critical role in maintaining skin and hair by regulating the differentiation of epithelial stem cells, as well as a putative role in regulating gene expression via chromatin remodeling.

Figure 1. Schematic representation of rat HR structural and functional domains.

Repression domains (RD1, 236-450; RD2, 750-864; RD3, 864-981); TR-interacting domains (TR-ID1, 816-830; TR-ID2, 1026-1038); ROR-interacting domains, ROR-ID1, 586-590; ROR-ID2, 778-782); cysteine-rich domain, 587-712; JmjC domain, 964-1175. Note that rat HR is 1207 amino acids, mouse and human Hr initiate at an internal AUG (amino acid 27 in rat Hr) and are 1182 and 1189 amino acids, respectively.

Figure 2. Model for HR action in hair regrowth.

A) Onset of phenotype in Hr knockout mice. Note that initial hair growth is normal, but after the first hair cycle (around P17) the hair is shed and does not regrow. Hr-rhino and knockout mice get progressively more wrinkled with age. P9, postnatal day 9; P19, postnatal day 19; P45, postnatal day 45; 8 mo, 8 months. B) Schematic representation of hair cycle. Wnt signaling initiates the transition from rest (telogen) to growth (anagen). C) Summary of HR protein expression through the hair cycle in relation to Wise and Soggy mRNA expression. Regression (catagen) is characterized by the upregulation of HR protein and concurrent downregulation of Wise/Soggy mRNA. HR protein expression during rest (telogen) is predicted to repress Wise/Soggy mRNA expression, allowing Wnt activation. Subsequent to the reinitiation of hair growth (anagen), HR protein is downregulated while Wise/Soggy mRNA increases, resulting in a transient decrease in Wnt signaling required for proper hair growth. In Hr mutants, uncontrolled expression of Wise/Soggy and possibly other Wnt inhibitors prevents hair regrowth by suppressing Wnt signaling. Figure adapted from (Thompson et al., 2006).

Figure 3. Mutant Hr alleles from human patients lack corepressor activity.

Naturally-occurring HR mutants tested for corepressor activity. Top, schematic representation of human HR protein (hHR) functional domains. Bottom, positions of mutated residues and altered amino acids. Blue indicates polymorphism, red indicates missense mutation. Mutants were tested for the ability to mediate repression by VDR and TR. Mutations in human HR were tested with VDR, mutants in rat HR (corresponding to the mutations found in human Hr alleles) were tested with TR (boxed). All proteins were expressed at equivalent levels except for P69S. All expressed proteins retain interaction with TR and VDR. In general, mutants lack corepressor activity, polymorphisms retain corepressor activity. Missense mutants (red): E583V (Paradisi et al., 2003); C622G/ C642G(rat) (Aita et al., 2000); N970S/N988S(rat) (Kruse et al., 1999); D1012N/D1030N(rat) (Klein et al., 2002); V1056M (Zlotogorski et al., 2002); V1136D/V1154D(rat) (Cichon et al., 1998), Q1176X (Henn et al., 2002). Polymorphisms (blue): P69S, C397Y/C422Y(rat), A576V, E591G/E611G(rat), R620Q, T1022A (Hillmer et al., 2002).