Submitted to the Department of Developmental Biology.
Ph.D. Stanford University 2013
To meet host metabolic demands after birth, organs like pancreatic islets increase their physiological function and mass. Compared to fetal islet development, however, little is known about mechanisms governing neonatal islet maturation and expansion. Here I demonstrate calcineurin/Nuclear Factor of Activated T-cells (Cn/NFAT) signaling regulates both [beta]-cell maturation and proliferation in neonatal mice and humans. Inactivation of the gene encoding the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), in mouse islets resulted in defective dense core granule biogenesis, impaired insulin secretion, and reduced neonatal [beta]-cell proliferation and mass, culminating in lethal, early-onset diabetes. [beta]-cells lacking Cnb1 failed to express genes required for insulin storage and secretion, as well as neonatal replication. Tacrolimus, a calcineurin inhibitor and widely used immunosuppressant, reduces human [beta]-cell secretion and promotes diabetes, toxicities without a clear molecular basis. Exposure of mouse and human islets to tacrolimus reduced expression of genes encoding factors essential for insulin dense core granule formation and secretion, and neonatal [beta]-cell proliferation consistent with our genetic studies. Chromatin immunoprecipitation and other molecular studies revealed these genes as novel, direct NFAT targets in neonatal mouse and human islets. Thus, calcineurin/NFAT signaling coordinately regulates factors that govern [beta]-cell maturation and proliferation, revealing unique models for the pathogenesis and therapy of diabetes mellitus and diverse human islet diseases.