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Differentiation of early foregut endoderm into pancreatic endocrine and exocrine cells depends on a cascade of gene activation events controlled by various transcription factors. Prior in vitro analysis has suggested that the forkhead/winged helix transcription factor Foxa2 (formerly HNF-3beta) is a major upstream regulator of Pdx1, a homeobox gene essential for pancreatic development. Pdx1 is also essential for the maintenance of glucose homeostasis, as its human orthologue, IPF-1, is mutated in a subset of patients with early-onset type 2 diabetes (MODY4). To analyze the Foxa2/Pdx1 regulatory cascade during pancreatic beta-cell differentiation, we used conditional gene ablation of Foxa2 in mice. We demonstrated that the deletion of Foxa2 in beta-cell-specific knockout mice results in downregulation of Pdx1 mRNA and subsequent reduction of PDX-1 protein levels in islets. These data represent the first in vivo demonstration that Foxa2 acts upstream of Pdx1 in the differentiated beta-cell. Diabetes 51:2546-2551, 2002
Hprt, hypoxanthine-phosphoribosyltransferase; IPF-1, insulin promoter factor 1; Pn, postnatal day n; PBT, PBS containing 0.1% BSA and 0.22% Triton X-100; p.c., post coitum; PP, pancreatic polypeptide.
The mammalian pancreas is comprised of exocrine, endocrine, and ductal cell types that are of endodermal origin. During mouse development, dorsal and ventral pancreatic primordia first appear as evaginations of the foregut endoderm on day 9 post coitum (p.c.). Prepancreatic endoderm is patterned in a stepwise manner, first by signals from mesoderm/ectoderm on day 7.5 p.c., and then by signals from the notochord during the next day (1,2). Shortly thereafter, endothelial cells provide additional signals to induce the prepatterned endoderm to differentiate into insulin-expressing beta-cells (3). The exocrine pancreas is composed of a ductal system and a relatively homogenous population of acinar cells that secrete digestive enzymes. The endocrine compartment is organized into clusters of cells called islets of Langerhans that differentiate into four endocrine cell types-the alpha, beta, delta, and pancreatic polypeptide (PP) cells-which express glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively (4,5).
The development of the endocrine compartment is controlled by a hierarchy of transcription factors that include Isl1, Nkx2.2, Pax4, Pax6, and NeuroD/BETA2 (6-8). These factors are expressed during the early stages of pancreas development, and function at several levels of endocrine cell differentiation. However, the initial steps of pancreatic development are not perturbed in mice homozygous...