Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types.
All pancreatic endocrine cells, producing glucagon, insulin, somatostatin, or PP, differentiate from Pdx1+ progenitors that transiently express Neurogenin3. To understand whether the competence of pancreatic progenitors changes over time, we generated transgenic mice expressing a tamoxifen-inducible Ngn3 fusion protein under the control of the pdx1 promoter and backcrossed the transgene into the ngn3(-/-) background, devoid of endogenous endocrine cells. Early activation of Ngn3-ER(TM) almost exclusively induced glucagon+ cells, while depleting the pool of pancreas progenitors. As from E11.5, Pdx1+ progenitors became competent to differentiate into insulin+ and PP+ cells. Somatostatin+ cells were generated from E14.5, while the competence to make glucagon+ cells was dramatically decreased. Hence, pancreas progenitors, similar to retinal or cortical progenitors, go through competence states that each allow the generation of a subset of cell types. We further show that the progenitors acquire competence to generate late-born cells in a mechanism that is intrinsic to the epithelium.
Johansson
Kerstin A
KA
Swiss Institute for Experimental Cancer Research, 155 ch des Boveresses, 1066 Epalinges, Switzerland.
Dursun
Umut
U
Jordan
Nathalie
N
Gu
Guoqiang
G
Beermann
Friedrich
F
Gradwohl
Gérard
G
Grapin-Botton
Anne
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D004703:Endocrine System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D010187:Pancreatic Hormones / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D013004:Somatostatin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D005934:Glucagon; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D010187:Pancreatic Hormones; D013004:Somatostatin; D015534:Trans-Activators; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein