Foxc1 Ablated Mice Are Anhidrotic and Recapitulate Features of Human Miliaria Sweat Retention Disorder.
Sweat glands are critical for thermoregulation. The single tubular structure of sweat glands has a lower secretory portion and an upper reabsorptive duct leading to the secretory pore in the skin. Genes that determine sweat gland structure and function are largely unidentified. Here we report that a Fox family transcription factor, Foxc1, is obligate for appreciable sweat duct activity in mice. When Foxc1 was specifically ablated in skin, sweat glands appeared mature, but the mice were severely hypohidrotic. Morphologic analysis revealed that sweat ducts were blocked by hyperkeratotic or parakeratotic plugs. Consequently, lumens in ducts and secretory portions were dilated, and blisters and papules formed on the skin surface in the knockout mice. The phenotype was strikingly similar to the human sweat retention disorder miliaria. We further show that Foxc1 deficiency ectopically induces the expression of keratinocyte terminal differentiation markers in the duct luminal cells, which most likely contribute to keratotic plug formation. Among those differentiation markers, we show that Sprr2a transcription is directly repressed by overexpressed Foxc1 in keratinocytes. In summary, Foxc1 regulates sweat duct luminal cell differentiation, and mutant mice mimic miliaria and provide a possible animal model for its study.
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. Electronic address: cuic@mail.nih.gov.
Chang-Yi
CY
Cui
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Ryuga
R
Ishii
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Dean P
DP
Campbell
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Marc
M
Michel
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Yulan
Y
Piao
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Tsutomu
T
Kume
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
David
D
Schlessinger
D000818:Animals; D001707:Biopsy, Needle; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D005588:Fox-Fordyce Disease / Q000235:genetics* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics / Q000503:physiopathology*; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D013545:Sweat Glands / Q000196:embryology* / Q000473:pathology
D051858:Forkhead Transcription Factors; C496500:Foxa1 protein, mouse; C112890:Foxc1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D012333:RNA, Messenger