The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas.
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 alpha- and beta-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.
Collombat
Patrick
P
Max-Planck Institute for Biophysical Chemistry, Department of Molecular Cell Biology, Am Fassberg, 37077 Göttingen, Germany.
Hecksher-Sørensen
Jacob
J
Broccoli
Vania
V
Krull
Jens
J
Ponte
Ilaria
I
Mundiger
Tabea
T
Smith
Julian
J
Gruss
Peter
P
Serup
Palle
P
Mansouri
Ahmed
A
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000401:mortality; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D008297:Male; D051379:Mice; D051761:Paired Box Transcription Factors; D013004:Somatostatin / Q000096:biosynthesis*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
C469265:ARX protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; D014157:Transcription Factors; D013004:Somatostatin; D005934:Glucagon