Email updates

Keep up to date with the latest news and content from BMC Developmental Biology and BioMed Central.

Open Access Highly Accessed Research article

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

Simon Kordowich1, Patrick Collombat23*, Ahmed Mansouri14* and Palle Serup5

Author Affiliations

1 Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, D-37077 Göttingen, Germany

2 Diabetes Genetics team, Inserm U636, FR-06108 Nice, France

3 Université de Nice Sophia-Antipolis, FR-06108 Nice, France

4 Department of Clinical Neurophysiology, University of Göttingen, Robert-Koch Strasse 40, D-37075 Göttingen, Germany

5 Department of Developmental Biology, Hagedorn Research Institute, Niels Steensensvej 6, DK-2820 Gentofte, Denmark

For all author emails, please log on.

BMC Developmental Biology 2011, 11:52  doi:10.1186/1471-213X-11-52

Published: 31 August 2011

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 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.

Keywords:
Arx; Nkx2.2; somatostatin; ghrelin; Pax6; Pax4