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Hairless is a nuclear receptor corepressor essential for skin function.

Thompson CC - Nucl Recept Signal (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wyeth Research, Collegeville, Pennsylvania, USA. ThompsC5@wyeth.com

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.

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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).
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fig2: 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).

Mentions: Hr mRNA is most abundantly expressed in the skin and brain. Within the skin, Hr mRNA is localized to specific cells of the epidermis and hair follicles. Early in postnatal development, Hr mRNA is detected in epidermis, then expression is downregulated as development proceeds. In hair follicles, Hr mRNA is present throughout the hair cycle (Figure 2, described below) [Panteleyev et al., 2000]. Surprisingly, analysis of HR protein expression showed that follicles actively growing hair do not contain detectable HR protein [Beaudoin et al., 2005]. The discordance between Hr mRNA expression and protein expression points to posttranscriptional or posttranslational control of HR protein expression and/or stability. Indeed, recent work has shown a novel mechanism of translational regulation residing in a conserved upstream open reading frame (ORF), supporting the idea that regulation of HR protein expression is critical for its role in regulating hair growth [Wen et al., 2009]. The expression and function of HR protein in the skin has been studied in detail and is described below.


Hairless is a nuclear receptor corepressor essential for skin function.

Thompson CC - Nucl Recept Signal (2009)

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).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2807636&req=5

fig2: 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).
Mentions: Hr mRNA is most abundantly expressed in the skin and brain. Within the skin, Hr mRNA is localized to specific cells of the epidermis and hair follicles. Early in postnatal development, Hr mRNA is detected in epidermis, then expression is downregulated as development proceeds. In hair follicles, Hr mRNA is present throughout the hair cycle (Figure 2, described below) [Panteleyev et al., 2000]. Surprisingly, analysis of HR protein expression showed that follicles actively growing hair do not contain detectable HR protein [Beaudoin et al., 2005]. The discordance between Hr mRNA expression and protein expression points to posttranscriptional or posttranslational control of HR protein expression and/or stability. Indeed, recent work has shown a novel mechanism of translational regulation residing in a conserved upstream open reading frame (ORF), supporting the idea that regulation of HR protein expression is critical for its role in regulating hair growth [Wen et al., 2009]. The expression and function of HR protein in the skin has been studied in detail and is described below.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wyeth Research, Collegeville, Pennsylvania, USA. ThompsC5@wyeth.com

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.

Show MeSH
Related in: MedlinePlus