The mesenchyme controls the timing of pancreatic beta-cell differentiation.
The importance of mesenchymal-epithelial interactions in the proliferation of pancreatic progenitor cells is well established. Here, we provide evidence that the mesenchyme also controls the timing of beta-cell differentiation. When rat embryonic pancreatic epithelium was cultured without mesenchyme, we found first rapid induction in epithelial progenitor cells of the transcription factor neurogenin3 (Ngn3), a master gene controlling endocrine cell-fate decisions in progenitor cells; then beta-cell differentiation occurred. In the presence of mesenchyme, Ngn3 induction was delayed, and few beta-cells developed. This effect of the mesenchyme on Ngn3 induction was mediated by cell-cell contacts and required a functional Notch pathway. We then showed that associating Ngn3-expressing epithelial cells with mesenchyme resulted in poor beta-cell development via a mechanism mediated by soluble factors. Thus, in addition to its effect upstream of Ngn3, the mesenchyme regulated beta-cell differentiation downstream of Ngn3. In conclusion, these data indicate that the mesenchyme controls the timing of beta-cell differentiation both upstream and downstream of Ngn3.
Duvillié
Bertrand
B
Université Paris-Descartes, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale, E363, Hôpital Necker, Paris, France. duvillie@necker.fr
Attali
Myriam
M
Bounacer
Ali
A
Ravassard
Philippe
P
Basmaciogullari
Annie
A
Scharfmann
Raphael
R
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000502:physiology; D002450:Cell Communication; D002454:Cell Differentiation; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D008648:Mesoderm / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000502:physiology; D009924:Organ Culture Techniques; D010179:Pancreas / Q000196:embryology*; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; C498696:Neurog3 protein, rat