Genetic identification of a novel NeuroDl function in the early differentiation of islet α, PP and ε cells

Nkx2.2 and NeuroDl are vital for proper differentiation of pancreatic islet cell types. Nkx2.2-null mice fail to form p cells, have reduced numbers of alpha and PP cells and display an increase in ghrelin-producing E cells. NeuroDl-null mice display a reduction of alpha and beta cells after embryonic day (e) 17.5. To begin to determine the relative contributions of Nkx2.2 and NeuroD I in islet development, we generated Nkx2.2-/-; NeuroDl -/- double knockout (DKO) mice. As expected, the DKO mice fail to form [cells, similar to the Nkx2.2-null mice, suggesting that the Nkx2.2 phenotype may be dominant over the NeuroDl phenotype in the cells. Surprisingly, however, the alpha, PP and epsilon phenotypes of the Nkx2.2-null mice are partially rescued by the simultaneous elimination of NeuroDl, even at early developmental time points when NeuroDl null mice alone do not display a phenotype. Our results indicate that Nkx2.2 and NeuroDl 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 NeuroDl in regulating the specification of alpha, PP and epsilon cells. (c) 2007 Elsevier Inc. All rights reserved.