Abstract
Neurogenin 3 (Ngn3) is key for endocrine cell specification in the embryonic pancreas and induction of a neuroendocrine cell differentiation program by misexpression in adult pancreatic duct cells. We identify the gene encoding IA1, a zinc-finger transcription factor, as a direct target of Ngn3 and show that it forms a novel branch in the Ngn3-dependent endocrinogenic transcription factor network. During embryonic development of the pancreas, IA1 and Ngn3 exhibit nearly identical spatio-temporal expression patterns. However, embryos lacking Ngn3 fail to express IA1 in the pancreas. Upon ectopic expression in adult pancreatic duct cells Ngn3 binds to chromatin in the IA1 promoter region and activates transcription. Consistent with this direct effect, IA1 expression is normal in embryos mutant for NeuroD1, Arx, Pax4 and Pax6, regulators operating downstream of Ngn3. IA1 is an effector of Ngn3 function as inhibition of IA1 expression in embryonic pancreas decreases the formation of insulin- and glucagon-positive cells by 40%, while its ectopic expression amplifies neuroendocrine cell differentiation by Ngn3 in adult duct cells. IA1 is therefore a novel Ngn3-regulated factor required for normal differentiation of pancreatic endocrine cells.
Publication types
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Research Support, N.I.H., Extramural
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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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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Basic Helix-Loop-Helix Transcription Factors / physiology*
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Cell Differentiation*
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Eye Proteins / metabolism
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Female
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Gene Expression Regulation, Developmental*
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Glucagon / metabolism
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Homeodomain Proteins / metabolism
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Insulin / metabolism
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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, Transgenic
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / physiology*
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PAX6 Transcription Factor
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Paired Box Transcription Factors / metabolism
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Pancreatic Ducts / cytology
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Pancreatic Ducts / metabolism
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Pregnancy
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / metabolism
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Transcription, Genetic
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Zinc Fingers
Substances
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ARX protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Eye Proteins
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Homeodomain Proteins
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Insulin
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Nerve Tissue Proteins
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Neurod1 protein, mouse
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Neurog3 protein, mouse
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PAX6 Transcription Factor
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PAX6 protein, human
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Paired Box Transcription Factors
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Pax4 protein, mouse
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Pax6 protein, mouse
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Repressor Proteins
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Transcription Factors
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INSM1 protein, human
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Glucagon