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

BMC Developmental Biology

Palle Serup²  Ahmed Mansouri¹  Patrick Collombat³  Simon Kordowich⁴ 

[1] Department of Clinical Neurophysiology, University of Göttingen, Robert-Koch Strasse 40, D-37075 Göttingen, Germany;Department of Developmental Biology, Hagedorn Research Institute, Niels Steensensvej 6, DK-2820 Gentofte, Denmark;Université de Nice Sophia-Antipolis, FR-06108 Nice, France;Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, D-37077 Göttingen, Germany

关键词: Pax4;    Pax6;    ghrelin;    somatostatin;    Nkx2.2;    Arx;   

Others  :  1087462
DOI  :  10.1186/1471-213X-11-52

 received in 2011-05-06, accepted in 2011-08-31,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Kordowich et al; licensee BioMed Central Ltd.

【 图 表 】

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