arx and nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatinghrelin co-expressing cell lineagearx和nkx2.2化合物缺乏重定向胰α-和β细胞分化somatostatinghrelin共同表达细胞谱系.pdfVIP

Kordowich et al. BMC Developmental Biology 2011, 11:52 /1471-213X/11/52 RESEARCH ARTICLE Open Access Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage 1 2,3*† 1,4*† 5† Simon Kordowich , Patrick Collombat , Ahmed Mansouri and Palle Serup Abstract Background: Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented. 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. Results: 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. Conclusions: Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and