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First published online 1 June 2005
doi: 10.1242/dev.01870
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- and ß-cell lineages in the mouse endocrine pancreas
1 Max-Planck Institute for Biophysical Chemistry, Department of Molecular Cell
Biology, Am Fassberg, 37077 Göttingen, Germany
2 Hagedorn Research Institute, Department of Developmental Biology, Niels
Steensensvej 6, DK-2820 Gentofte, Denmark
3 DIBIT, San Raffaele Scientific Institute, Via Olgenittina 58, I-20132 Milano,
Italy
4 Centre de Biologie du Développement, UMR-5547 CNRS-Université P.
Sabatier, 118 Route de Narbonne, F-31062 Toulouse, Cedex 04, France
* Author for correspondence (e-mail: amansou{at}gwdg.de)
Accepted 19 April 2005
The specification of the different mouse pancreatic endocrine subtypes is
determined by the concerted activities of transcription factors. However, the
molecular mechanisms regulating endocrine fate allocation remain unclear. In
the present study, we uncover the molecular consequences of the simultaneous
depletion of Arx and Pax4 activity during pancreas development. Our findings
reveal a so far unrecognized essential role of the paired-box-encoding
Pax4 gene. Specifically, in the combined absence of Arx and
Pax4, an early-onset loss of mature 
- and ß-cells occurs
in the endocrine pancreas, concomitantly with a virtually exclusive generation
of somatostatin-producing cells. Furthermore, despite normal development of
the PP-cells in the double-mutant embryos, an atypical expression of the
pancreatic polypeptide (PP) hormone was observed in somatostatin-labelled
cells after birth. Additional characterizations indicate that such an
expression of PP was related to the onset of feeding, thereby unravelling an
epigenetic control. Finally, our data provide evidence that both Arx and Pax4
act as transcriptional repressors that control the expression level of one
another, thereby mediating proper endocrine fate allocation.
Key words: Endocrine pancreas development, Arx, Pax4, Mouse, Hyperglycaemia, Fate specification
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