Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1.
Body temperature is maintained in a narrow range in mammals, primarily controlled by sweating. In humans, the dynamic thermoregulatory organ, comprised of 2-4 million sweat glands distributed over the body, can secrete up to 4 L of sweat per day, thereby making it possible to withstand high temperatures and endure prolonged physical stress (e.g., long-distance running). The genetic basis for sweat gland function, however, is largely unknown. We find that the forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. Despite continued sweat gland morphogenesis, ablation of FoxA1 in mice results in absolute anihidrosis (lack of sweating). This inability to sweat is accompanied by down-regulation of the Na-K-Cl cotransporter 1 (Nkcc1) and the Ca(2+)-activated anion channel Bestrophin 2 (Best2), as well as glycoprotein accumulation in gland lumens and ducts. Furthermore, Best2-deficient mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca(2+) are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One feature, via Best2, catalyzes a bicarbonate gradient that could help to drive calcium-associated ionic transport; the other, requiring Nkcc1, facilitates monovalent ion exchange into sweat. These mechanistic components can be pharmaceutical targets to defend against hyperthermia and alleviate defective thermoregulation in the elderly, and may provide a model relevant to more complex secretory processes.
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. cuic@mail.nih.gov
Chang-Yi
CY
Cui
Victoria
V
Childress
Yulan
Y
Piao
Marc
M
Michel
Adiv A
AA
Johnson
Makoto
M
Kunisada
Minoru S H
MS
Ko
Klaus H
KH
Kaestner
Alan D
AD
Marmorstein
David
D
Schlessinger
D000704:Analysis of Variance; D000818:Animals; D000075002:Bestrophins; D015153:Blotting, Western; D001833:Body Temperature Regulation / Q000502:physiology*; D018118:Chloride Channels / Q000378:metabolism*; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D005136:Eye Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005697:Galactosides; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D007211:Indoles; D051379:Mice; D008954:Models, Biological; D060888:Real-Time Polymerase Chain Reaction; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064506:Solute Carrier Family 12, Member 2; D013546:Sweating / Q000235:genetics / Q000502:physiology*
C497463:Best2 protein, mouse; D000075002:Bestrophins; D018118:Chloride Channels; D017931:DNA Primers; D005136:Eye Proteins; C496500:Foxa1 protein, mouse; D005697:Galactosides; D051541:Hepatocyte Nuclear Factor 3-alpha; D007211:Indoles; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside