Dataset Information

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation.

ABSTRACT: In most tissues, the prevailing view is that stem cell (SC) niches are generated by signals from within the nearby tissue environment. Here, we define genetic changes altered in hair follicle (HF) SCs in mice treated with a potent SC activator, cyclosporine A (CSA), which inhibits the phosphatase calcineurin (CN) and the activity of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). We show that CN/Nfatc1 regulates expression of prolactin receptor (Prlr) and that canonical activation of Prlr and its downstream signaling via Jak/Stat5 drives quiescence of HF SCs during pregnancy and lactation, when serum prolactin (Prl) levels are highly elevated. Using Prl injections and genetic/pharmacological loss-of-function experiments in mice, we show that Prl signaling stalls follicular SC activation through its activity in the skin epithelium. Our findings define a unique CN-Nfatc1-Prlr-Stat5 molecular circuitry that promotes persistent SC quiescence in the skin.

SUBMITTER: Goldstein J

PROVIDER: S-EPMC4018496 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation.

Goldstein Jill J Fletcher Sean S Roth Eve E Wu Christine C Chun Andrew A Horsley Valerie V

Genes & development 20140414 9

In most tissues, the prevailing view is that stem cell (SC) niches are generated by signals from within the nearby tissue environment. Here, we define genetic changes altered in hair follicle (HF) SCs in mice treated with a potent SC activator, cyclosporine A (CSA), which inhibits the phosphatase calcineurin (CN) and the activity of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). We show that CN/Nfatc1 regulates expression of prolactin receptor (Prlr) and that canonical ...[more]

PMID: 24732379

Similar Datasets

Project description:Semilunar valve malformations are common human congenital heart defects. Bicuspid aortic valves occur in 2-3% of the population, and pulmonic valve stenosis constitutes 10% of all congenital heart disease in adults (Brickner et al., 2000) [1]. Semilunar valve defects cause valve regurgitation, stenosis, or calcification, leading to endocarditis or congestive heart failure. These complications often require prolonged medical treatment or surgical intervention. Despite the medical importance of valve disease, the regulatory pathways governing semilunar valve development are not entirely clear. In this report we investigated the spatiotemporal role of calcineurin/Nfatc1 signaling in semilunar valve development. We generated conditional knockout mice with calcineurin gene disrupted in various tissues during semilunar valve development. Our studies showed that calcineurin/Nfatc1 pathway signals in the secondary heart field (SHF) but not in the outflow tract myocardium or neural crest cells to regulate semilunar valve morphogenesis. Without SHF calcineurin/Nfatc1 signaling, the conal endocardial cushions-the site of prospective semilunar valve formation--first develop and then regress due to apoptosis, resulting in a striking phenotype with complete absence of the aortic and pulmonic valves, severe valve regurgitation, and perinatal lethality. This role of calcineurin/Nfatc1 signaling in the SHF is different from the requirement of calcineurin/Nfatc1 in the endocardium for semilunar valve formation (Chang et al., 2004) [2], indicating that calcineurin/Nfatc1 signals in multiple tissues to organize semilunar valve development. Also, our studies suggest distinct mechanisms of calcineurin/Nfat signaling for semilunar and atrioventricular valve morphogenesis. Therefore, we demonstrate a novel developmental mechanism in which calcineurin signals through Nfatc1 in the secondary heart field to promote semilunar valve morphogenesis, revealing a new supportive role of the secondary heart field for semilunar valve formation.

Project description:Background & aimsOncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis.MethodsWe analyzed pancreatic tissues from Kras(G12D);pdx1-Cre and Kras(G12D);NFATc1(Δ/Δ);pdx1-Cre mice after intraperitoneal administration of caerulein, vs cyclosporin A or dimethyl sulfoxide (controls). Induction of EGFR signaling and its effects on the expression of Nuclear factor of activated T cells c1 (NFATc1) or SOX9 were investigated by quantitative reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue.ResultsEGFR activation induced expression of NFATc1 in metaplastic areas from patients with chronic pancreatitis and in pancreatic tissue from Kras(G12D) mice. EGFR signaling also promoted formation of a complex between NFATc1 and C-JUN in dedifferentiating mouse acinar cells, leading to activation of Sox9 transcription and induction of acinar-ductal metaplasia. Pharmacologic inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar-ductal transdifferentiation and pancreatic cancer initiation in mice.ConclusionsEGFR signaling induces expression of NFATc1 and Sox9, leading to acinar cell transdifferentiation and initiation of pancreatic cancer. Strategies designed to disrupt this pathway might be developed to prevent pancreatic cancer initiation in high-risk patients with chronic pancreatitis.

Dataset Information

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation.

Publications

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets