TY - JOUR TI - Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development AU - Churchill, Angela J AU - Gutiérrez, Giselle Dominguez AU - Singer, Ruth A AU - Lorberbaum, David S AU - Fischer, Kevin A AU - Sussel, Lori A2 - Blackburn, Clare VL - 6 PY - 2017 DA - 2017/01/10 SP - e20010 C1 - eLife 2017;6:e20010 DO - 10.7554/eLife.20010 UR - https://doi.org/10.7554/eLife.20010 AB - Many pancreatic transcription factors that are essential for islet cell differentiation have been well characterized; however, because they are often expressed in several different cell populations, their functional hierarchy remains unclear. To parse out the spatiotemporal regulation of islet cell differentiation, we used a Neurog3-Cre allele to ablate Nkx2.2, one of the earliest and most broadly expressed islet transcription factors, specifically in the Neurog3+ endocrine progenitor lineage (Nkx2.2△endo). Remarkably, many essential components of the β cell transcriptional network that were down-regulated in the Nkx2.2KO mice, were maintained in the Nkx2.2△endo mice - yet the Nkx2.2△endo mice displayed defective β cell differentiation and recapitulated the Nkx2.2KO phenotype. This suggests that Nkx2.2 is not only required in the early pancreatic progenitors, but has additional essential activities within the endocrine progenitor population. Consistently, we demonstrate Nkx2.2 functions as an integral component of a modular regulatory program to correctly specify pancreatic islet cell fates. KW - Transcriptional networks KW - pancreatic islet KW - beta cells JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -