Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1

Chang Yi Cui, Victoria Childress, Yulan Piao, Marc Michel, Adiv A. Johnson, Makoto Kunisada, Minoru Ko, Klaus H. Kaestner, Alan D. Marmorstein, David Schlessinger

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1199-1203
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number4
DOIs
Publication statusPublished - 2012 Jan 24
Externally publishedYes

Fingerprint

Sodium-Potassium-Chloride Symporters
Forkhead Transcription Factors
Sweat
Anions
Sweat Glands
Sweating
Glycoproteins
Hypohidrosis
Potassium Chloride
Body Temperature Regulation
Secretory Pathway
Ion Exchange
Bicarbonates
Body Temperature
Morphogenesis
Sodium Chloride
Running
Mammals
Fever
Down-Regulation

Keywords

  • Cystic fibrosis
  • Ectodysplasin
  • Idiopathic-acquired generalized anhidrosis

ASJC Scopus subject areas

  • General

Cite this

Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1. / Cui, Chang Yi; Childress, Victoria; Piao, Yulan; Michel, Marc; Johnson, Adiv A.; Kunisada, Makoto; Ko, Minoru; Kaestner, Klaus H.; Marmorstein, Alan D.; Schlessinger, David.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 4, 24.01.2012, p. 1199-1203.

Research output: Contribution to journalArticle

Cui, Chang Yi ; Childress, Victoria ; Piao, Yulan ; Michel, Marc ; Johnson, Adiv A. ; Kunisada, Makoto ; Ko, Minoru ; Kaestner, Klaus H. ; Marmorstein, Alan D. ; Schlessinger, David. / Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 4. pp. 1199-1203.
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AU - Michel, Marc

AU - Johnson, Adiv A.

AU - Kunisada, Makoto

AU - Ko, Minoru

AU - Kaestner, Klaus H.

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