- In recent years, significant progress has been achieved in the understanding of the morphogenic aspects of hair follicle biology, nevertheless, the cellular, molecular and genetic aspects of hair growth control remain largely unknown, Our previous studies implicate the mouse hairless (hr) gene as a key factor in coordinating basic cellular processes during hair follicle catagen, including club hair formation, maintenance of dermal papilla-epithelial integrity, inner root sheath disintegration, and particularly, keratinocyte apoptosis in the hair matrix cells. In the hair follicle, hairless appears to function in the cellular transition to the first adult hair cycle. In its absence, in hairless (hr/hr) or rhino (rh/rh) mice, hair growth completely ceases, a new hair is never induced, and the result is a complete form of inherited atrichia. We have established that the disorder papular atrichia represents the human counterpart of the hairless and rhino mouse phenotypes, resulting from mutations in the hairless gene. However, at the molecular and cellular level, the mechanism(s) of function of the hairless protein remains largely unknown. Hairless is a single zinc-finger protein which is thought to function as a putative transcription factor. We have recently shown unequivocally that hairless is localized to the nucleus, and interestingly, that it is associated with the nuclear matrix. Protein analysis software has identified three LXXLL motifs, known as NR (nuclear receptor) boxes, which are signatures of the transcriptional coactivator family of proteins. We have compiled several lines of new evidence which implicate hairless in a pathway of genes regulated by the vitamin D receptor (VDR). These include the clinical and histological similarities between hairless mice and both VDR and retinoid X receptor (RXRa) null mice. In addition, we provide evidence that the human papular atrichia is clinically and histologically indistinguishable from vitamin D dependent rickets, with mutations in the VDR. Finally, we have identified a putative target pathway for hairless regulation which involves the upregulation of ornithine decarboxylase. We have combined our preliminary studies with several emerging lines of biological data to formulate a hypothesis which asks three questions. First, is hairless a DNA-binding protein, and if yes, what is its signature sequence? Secondly, is hairless a transcriptional coactivator, and if yes, what are its interaction partners? Finally, what are the downstream targets of hairless gene regulation? We anticipate that this approach will allow us to gain novel insights into the function of the hairless protein for the first time.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Moshell, Alan N
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Columbia University (N.Y.)
Schools of Medicine
New York
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Liu, Liang; Kim, Hyunmi; Casta, Alex et al. (2014) Hairless is a histone H3K9 demethylase. FASEB J 28:1534-42
Luke, Courtney T; Casta, Alexandre; Kim, Hyunmi et al. (2013) Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis. Exp Dermatol 22:644-9
Casta, Alexandre; Kim, Hyunmi; Luke, Courtney T et al. (2012) Hairless and NF?B form a positive feedback loop after UVB and TNF? stimulation. Photochem Photobiol 88:1173-83
Kim, Hyunmi; Casta, Alexandre; Tang, Xiuwei et al. (2012) Loss of hairless confers susceptibility to UVB-induced tumorigenesis via disruption of NF-kappaB signaling. PLoS One 7:e39691
Jahoda, Colin A B; Christiano, Angela M (2011) Niche crosstalk: intercellular signals at the hair follicle. Cell 146:678-81
Engelhard, Andrew; Bauer, Robert C; Casta, Alexandre et al. (2008) Ligand-independent regulation of the hairless promoter by vitamin D receptor. Photochem Photobiol 84:515-21
Kraemer, Liv; Wajid, Muhammad; Shimomura, Yutaka et al. (2008) Mutations in the hairless gene underlie APL in three families of Pakistani origin. J Dermatol Sci 50:25-30
Michailidis, Eleni; Theos, Amy; Zlotogorski, Abraham et al. (2007) Atrichia with papular lesions resulting from novel compound heterozygous mutations in the human hairless gene. Pediatr Dermatol 24:E79-82
Kim, Hyunmi; Wajid, Muhammad; Kraemer, Liv et al. (2007) Nonsense mutations in the hairless gene underlie APL in five families of Pakistani origin. J Dermatol Sci 48:207-11
Ashoor, G; Masse, M; Garcia Luciano, L M et al. (2006) A novel mutation in the 12(R)-lipoxygenase (ALOX12B) gene underlies nonbullous congenital ichthyosiform erythroderma. Br J Dermatol 155:198-200

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