Opposing actions of Arx and Pax4 in endocrine pancreas development (original) (raw)

  1. Patrick Collombat1,
  2. Ahmed Mansouri1,
  3. Jacob Hecksher-Sørensen2,
  4. Palle Serup2,
  5. Jens Krull1,
  6. Gerard Gradwohl3, and
  7. Peter Gruss1,4
  8. 1 Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany
  9. 2 Department of Developmental Biology, Hagedorn Research Institute, DK-2820 Gentofte, Denmark
  10. 3 Institut National de la Sante et de la Recherche Medicale U381, 67200 Strasbourg, France

Abstract

Genes encoding homeodomain-containing proteins potentially involved in endocrine pancreas development were isolated by combined in silico and nested-PCR approaches. One such transcription factor, Arx, exhibits _Ngn3_-dependent expression throughout endocrine pancreas development in α, β-precursor, and δ cells. We have used gene targeting in mouse embryonic stem cells to generate Arx loss-of-function mice. _Arx_-deficient animals are born at the expected Mendelian frequency, but develop early-onset hypoglycemia, dehydration, and weakness, and die 2 d after birth. Immunohistological analysis of pancreas from Arx mutants reveals an early-onset loss of mature endocrine α cells with a concomitant increase in β-and δ-cell numbers, whereas islet morphology remains intact. Our study indicates a requirement of Arx for α-cell fate acquisition and a repressive action on β-and δ-cell destiny, which is exactly the opposite of the action of Pax4 in endocrine commitment. Using multiplex reverse transcriptase PCR (RT-PCR), we demonstrate an accumulation of Pax4 and Arx transcripts in Arx and Pax4 mutant mice, respectively. We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts.

Footnotes