Dissecting the role of glucocorticoids on pancreas development.
To determine whether glucocorticoids are involved in pancreas development, glucocorticoid treatment of rat pancreatic buds in vitro was combined with the analysis of transgenic mice lacking the glucocorticoid receptor (GR) in specific pancreatic cells. In vitro treatment of embryonic pancreata with dexamethasone, a glucocorticoid agonist, induced a decrease of insulin-expressing cell numbers and a doubling of acinar cell area, indicating that glucocorticoids favored acinar differentiation; in line with this, expression of Pdx-1, Pax-6, and Nkx6.1 was downregulated, whereas the mRNA levels of Ptf1-p48 and Hes-1 were increased. The selective inactivation of the GR gene in insulin-expressing beta-cells in mice (using a RIP-Cre transgene) had no measurable consequences on beta- or alpha-cell mass, whereas the absence of GR in the expression domain of Pdx-1 (Pdx-Cre transgene) led to a twofold increased beta-cell mass, with increased islet numbers and size but normal alpha-cell mass in adults. These results demonstrate that glucocorticoids play an important role in pancreatic beta-cell lineage, acting before hormone gene expression onset and possibly also modulating the balance between endocrine and exocrine cell differentiation.
INSERM U457, Hôpital Robert Debré, Paris F 75019, France.
Emilie
E
Gesina
François
F
Tronche
Pedro
P
Herrera
Belinda
B
Duchene
Willemène
W
Tales
Paul
P
Czernichow
Bernadette
B
Breant
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005136:Eye Proteins; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics
D005136:Eye Proteins; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D007328:Insulin; C491328:Nkx6-1 protein, mouse; C491327:Nkx6-1 protein, rat; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; C000605733:Pax6 protein, rat; D012097:Repressor Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D003907:Dexamethasone