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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Cell Differentiation / genetics*
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Endocrine System / cytology
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Endocrine System / embryology*
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Endocrine System / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / metabolism*
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Female
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Gene Expression Regulation, Developmental / genetics
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Glucagon / metabolism
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Homeodomain Proteins / genetics
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Insulin / metabolism
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Insulin Secretion
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Islets of Langerhans / cytology
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Islets of Langerhans / embryology
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Islets of Langerhans / metabolism
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Male
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / genetics*
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Pancreas / cytology
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Pancreas / embryology*
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Pancreas / metabolism
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Pancreatic Hormones / metabolism
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Promoter Regions, Genetic / genetics
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Somatostatin / metabolism
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Stem Cells / cytology
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Stem Cells / metabolism*
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Time Factors
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Trans-Activators / genetics
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Homeodomain Proteins
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Insulin
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Nerve Tissue Proteins
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Neurog3 protein, mouse
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Pancreatic Hormones
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
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Somatostatin
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Glucagon