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. Morphological analysis revealed that 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 human sweat retention disorder miliaria. We further found that Foxc1 deficiency ectopically induced the expression of keratinocyte terminal differentiation markers in the luminal duct cells, which most likely contributed to keratotic plug formation. In summary, Foxc1 regulates sweat duct luminal cell differentiation, and mutant mice may provide a model for miliaria. Wild Type vs Foxc1 cKO mouse footpads