Genetic identification of a novel NeuroD1 function in the early differentiation of islet alpha, PP and epsilon cells |
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Authors: | Chao Christina S Loomis Zoe L Lee Jacqueline E Sussel Lori |
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Affiliation: | aUniversity of Colorado at Denver and Health Science Center, Biochemistry and Molecular Genetics Department, Aurora, CO 80045, USA;bMedical Scientist Training Program and Cell and Developmental Biology Program, UCHSC, Aurora, CO 80045, USA;cUniversity of Colorado at Boulder, Department of Molecular, Cellular, and Developmental Biology, Boulder, CO 80309, USA |
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Abstract: | Nkx2.2 and NeuroD1 are vital for proper differentiation of pancreatic islet cell types. Nkx2.2-null mice fail to form β cells, have reduced numbers of α and PP cells and display an increase in ghrelin-producing ε cells. NeuroD1-null mice display a reduction of α and β cells after embryonic day (e) 17.5. To begin to determine the relative contributions of Nkx2.2 and NeuroD1 in islet development, we generated Nkx2.2−/−;NeuroD1−/− double knockout (DKO) mice. As expected, the DKO mice fail to form β cells, similar to the Nkx2.2-null mice, suggesting that the Nkx2.2 phenotype may be dominant over the NeuroD1 phenotype in the β cells. Surprisingly, however, the α, PP and ε phenotypes of the Nkx2.2-null mice are partially rescued by the simultaneous elimination of NeuroD1, even at early developmental time points when NeuroD1 null mice alone do not display a phenotype. Our results indicate that Nkx2.2 and NeuroD1 interact to regulate pancreatic islet cell fates, and this epistatic relationship is cell-type dependent. Furthermore, this study reveals a previously unappreciated early function of NeuroD1 in regulating the specification of α, PP and ε cells. |
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Keywords: | Nkx2.2 NeuroD1 Islet development α Cells Cell differentiation Glucagon Ghrelin Genetic analysis |
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