Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage

Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of Nkx2.2/Arx single- and double-mutants but also of Pax6-deficient animals.We show that most of the ghrelin+ cells emerging in pancreata of Nkx2.2- and Pax6-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In Nkx2.2-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of Arx in committed beta-cells. The combined loss of Nkx2.2 and Arx likewise results in the formation of a hyperplastic ghrelin+ cell population at the expense of mature alpha- and beta-cells. Surprisingly, such Nkx2.2-/-Arx- ghrelin+ cells also express the somatostatin hormone.Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and Arx in early committed beta- and alpha-cell, respectively. Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells.The pancreas is comprised of acinar and duct cells (exocrine compartment), producing and transporting digestive enzymes and bicarbonate, as well as endocrine cells, which secrete hormones to the blood stream. The latter are aggregated into scattered clusters of cells, termed islets of Langerhans. These are typically composed of five cell subtypes, including alpha-, beta-, delta-, epsilon- and PP-cells that produce the hormones glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide (PP), respectively. Insulin and glucagon are secreted co-ordinately to control glucose homeostasis, whereas somatostatin and PP regulate the secretion of other hormones and of exocrine enzymes [1-5]. The hormone ghrelin has been shown to possess orexigenic properties and to play a role in glucose-stimulated insulin secretion [6,7].During pancreas development,