The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas

Abstract

The mammalian pancreas contains two distinct cell populations: endocrine cells which secrete hormones into the bloodstream, and exocrine cells, which secrete enzymes into the digestive tract. The four endocrine cell types found in the adult pancreas-(alpha, beta, delta and PP-synthesize glucagon, insulin, somatostatin and pancreatic polypeptide, respectively. All of these endocrine cells arise from common multipotent precursors, which coexpress several hormones when they start to differentiate. Expression of some homeobox genes in the early developing pancreas has been reported. The Pax4 gene is expressed in the early pancreas, but is later restricted to beta cells. Inactivation of Pax4 by homologous recombination results in the absence of mature insulin- and somatostatin-producing cells (beta and delta, respectively) in the pancreas of Pax4 homozygous mutant mice, but glucagon-producing alpha cells are present in considerably higher numbers. We propose that the early expression of Pax4 in a subset of endocrine progenitors is essential for the differentiation of the beta and delta cell lineages. A default pathway would explain the elevated number of alpha cells in the absence of Pax4.

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

“…The paired-box transcription factors, Pax4 and Pax6, also play important roles in the specification of the four endocrine lineages. Pax6 expression by endocrine progenitor cells is important for the formation of all endocrine lineages, particularly ␣ cells (30), while Pax4 is required for the formation of ␤ and ␦ cells (31).…”

Nestin expression in pancreatic endocrine and exocrine cells of mice lacking glucagon signaling

“…The fact that islet cells and neurons have similar molecular phenotypes (Ahlgren et al, 1997;Alpert et al, 1988;Gradwohl et al, 2000;Naya et al, 1997;Sander et al, 2000;Sosa-Pineda et al, 1997;Sussel et al, 1998;Turque et al, 1994) raised the possibility that precursor cells of islets, like those of brain, express the intermediate filament nestin (Cattaneo and McKay, 1990;Lendahl et al, 1990), a classical marker of neuronal stem cells. This possibility was supported by the discovery of nestin ϩ cells in epithelial cells of the pancreatic bud of mouse embryos from e-10 to e-15 (Esni et al, 2004), raising the prospect that these cells were endocrine precursor cells.…”

Reprogrammation des cellules pancréatiques en cellules β

“…De plus amples analyses indiquèrent qu'au cours du développement embryonnaire, une compétition entre Arx et Pax4 est à l'origine de la sélection des différents lignages endocrines, Arx promouvant le destin α, Pax4 le lignage / [8,9].…”