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

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.

Autosomal Recessive Bestrophinopathy Is Not Associated With the Loss of Bestrophin-1 Anion Channel Function in a Patient With a NovelBEST1Mutation

“…[7][8][9] Monomers of Best1 oligomerize [10][11][12][13][14] to form a highly conserved homopentameric Ca 2þ -activated ion channel. 8,9 Data from heterologous systems, 15,16 primary human RPE cell culture, 17,18 mouse models, 19,20 the structurally similar paralog bestrophin-2, 21,22 as well as recently published crystal structures 8,9 all unambiguously demonstrate that mammalian Best1 is a calcium-activated anion channel. In addition to functioning as an anion channel, Best1 regulates intracellular Ca 2þ signaling and influences Ca 2þ homeostasis.…”

Involvement of Wnt, Eda and Shh at defined stages of sweat gland development

“…Sweat secretion requires coordinated action of sympathetic nerve impulses, regulatory transcription factors and resultant secretory structures assembled during development (Cui et al, 2012;Sato et al, 1989). Sweat gland development includes successive induction, duct formation and secretory region formation (Fig.…”

“…The other pathway known to be involved in sweat gland maturation, which requires Foxa1, acts at the late stage of development of sweating capacity (Cui et al, 2012). In Shh mutant mice, as in wild type, immunostaining revealed nuclear localization of Foxa1 in scattered developing secretory cells (supplementary material Fig.…”

“…Among the possible factors to be assessed are: specific local niche matrices; pre-determinative differences in effectors in placodes; and the involvement of additional pathways such as that regulating sweating capacity, which is initiated by FoxA1 (for example) (Cui et al, 2012). However, the level and/or timing of Shh expression might be an important effector.…”

Control of Outflow Resistance by Soluble Adenylyl Cyclase

“…7 Bestrophin-2 (Best2) is expressed in a number of organs, including the colon, parotid gland, sweat gland, olfactory, and the eye. 11,[14][15][16] In the eye, Best2 is found exclusively in the nonpigmented epithelium (NPE) of the ciliary body (CB). 11,17 We have shown that Best2 functions as a bicarbonate channel.…”