Project description: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 liters of sweat per day1, thereby making it possible to withstand high temperatures and run long distances. The genetic basis for sweat gland function, however, is largely unknown. We find that a forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. When FoxA1 is ablated, mice are otherwise healthy and sweat gland morphogenesis occurs, but no sweating ensues, with the Nkcc1 sodium/potassium/chloride co-transporter and a specialized Ca2+-activated bicarbonate channel protein, Best2, both sharply down-regulated, and glycoprotein accumulating in gland lumens and ducts. Furthermore, Best2 knockout mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca2+ are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One, 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 elderly2, and may provide a model relevant to more complex secretory processes. For expression profiling of FoxA1, hairless fore footpad skin (6) was collected from FoxA1 knockouts and wild-type littermates at P10, P14 and P31. Three skin samples from 3 embryos for each genotype at each time point were used for biological replicates. Total RNAs were isolated with Trizol (Invitrogen), precipitated by 7.5M LiCl (Ambion), and cyanine-3-labeled cRNAs were hybridized to the NIA Mouse 44K Microarray v3.0 (Agilent Technologies). Triplicate data were analyzed by ANOVA (6). Genes with FDR<0.05, fold difference>1.5 and mean log intensity>2.0 were considered to be significant.
Project description: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 liters of sweat per day1, thereby making it possible to withstand high temperatures and run long distances. The genetic basis for sweat gland function, however, is largely unknown. We find that a forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. When FoxA1 is ablated, mice are otherwise healthy and sweat gland morphogenesis occurs, but no sweating ensues, with the Nkcc1 sodium/potassium/chloride co-transporter and a specialized Ca2+-activated bicarbonate channel protein, Best2, both sharply down-regulated, and glycoprotein accumulating in gland lumens and ducts. Furthermore, Best2 knockout mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca2+ are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One, 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 elderly2, and may provide a model relevant to more complex secretory processes.
Project description:To understand the mechanisms through which JunB regulates Tregs-mediated immune regulation, we examined the global gene expression profiles in the JunB WT and KO Tregs by performing RNA sequencing (RNA-seq) analysis.
Project description:The SLICK1 mutation confers thermotolerance to cattle inheriting one or two copies of the gene. Results are unclear as to whether the mutation changes capacity of animals to undergo sweating during heat stress. Accordingly, differences in characteristics of sweat glands between slick and wildtype Holstein heifers was determined. There were no differences in the proportion of skin occupied by sweat glands but sweat glands from slick heifers had higher amounts of immunoreactive FOXA1 than wildtype heifers. FOXA1 is a transcription factor important for sweating. While results do not support the idea that the SLICK1 mutation changes the abundance of sweat glands in skin, it did affect functional properties of sweat glands, as indicated by increased abundance of immunoreactive FOXA1.
Project description:Sweat has a critical role in human body, including thermoregulation and maintenance of skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion resulting in severe skin conditions (pruritus and erythema). Bioactive peptide, pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and identified to activate adenylate cyclase in pituitary cells. In recent years, it was reported that PACAP increases sweat secretion via PAC1R in mice and promotes the translocation of AQP5 to the cell membrane through increasing intercellular [Ca2+] via PAC1R in NCL-SG3 cells. However, the intracellular signaling mechanisms by PACAP are poorly clarified. In this study, we used PAC1R knockout (KO) mice and wild-type (WT) mice to observe changes in AQP5 localization and gene expression in sweat gland by PACAP treatment. Immunohistochemistry revealed that PACAP promotes the translocation of AQP5 to lumen side in eccrine gland via PAC1R. Furthermore, PACAP up-regulates gene expression (Ptgs2, Kcnn2, Cacna1s) involved in sweat secretion in WT mice. Further, PACAP treatment down-regulated Chrna1 gene expression in PAC1R KO mice. These genes were found to be involved in multiple pathways related to sweating. Overall our data provide a solid basis for future research initiatives to develop new therapies to treat sweating disorders.