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

• Main Authors: Mansouri Ahmed, Collombat Patrick, Kordowich Simon, Serup Palle
• Format: Article
• Language: English
• Published: BMC 2011-08-01
• Series: BMC Developmental Biology
• Subjects: Arx; Nkx2.2; somatostatin; ghrelin; Pax6; Pax4
• Online Access: http://www.biomedcentral.com/1471-213X/11/52

<p>Abstract</p> <p>Background</p> <p>Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for <it>Arx </it>do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In <it>Nkx2.2 </it>mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented.</p> <p>Notably, <it>Arx </it>transcription is clearly enhanced in <it>Nkx2.2</it>-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of <it>Nkx2.2/Arx </it>single- and double-mutants but also of <it>Pax6</it>-deficient animals.</p> <p>Results</p> <p>We show that most of the ghrelin⁺cells emerging in pancreata of <it>Nkx2.2</it>- and <it>Pax6</it>-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In <it>Nkx2.2</it>-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of <it>Arx </it>in committed beta-cells. The combined loss of <it>Nkx2.2 </it>and <it>Arx </it>likewise results in the formation of a hyperplastic ghrelin⁺cell population at the expense of mature alpha- and beta-cells. Surprisingly, such <it>Nkx2.2^-/-Arx^-</it>ghrelin⁺cells also express the somatostatin hormone.</p> <p>Conclusions</p> <p>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 <it>Arx </it>gene activity in early committed beta-cells.</p>