title: Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types.
abstract: 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.
authors.affiliation: Swiss Institute for Experimental Cancer Research, 155 ch des Boveresses, 1066 Epalinges, Switzerland.
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Johansson
authors.forename: Umut
authors.initials: U
authors.lastname: Dursun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jordan
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.forename: Friedrich
authors.initials: F
authors.lastname: Beermann
authors.forename: Gérard
authors.initials: G
authors.lastname: Gradwohl
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
mesh_terms: 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
chemical_list: 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