%0 Journal Article
%T Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain.
%A Abarinov V
%A Levine JA
%A Churchill AJ
%A Hopwood B
%A Deiter CS
%A Guney MA
%A Wells KL
%A Schrunk JM
%A Guo Y
%A Hammelman J
%A Gifford DK
%A Magnuson MA
%A Wichterle H
%A Sussel L
%J Genes Dev
%V 37
%N 11
%D 2023 06 1
%M 37364986
%F 12.89
%R 10.1101/gad.350569.123
%X The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive-especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that β cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of β cell precursors into mature, insulin-expressing β cells, resulting in overt neonatal diabetes. Within the adult β cell, the SD stimulates β cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for β cell function. These irregularities in β cell gene expression may be mediated via SD-contingent interactions with components of chromatin remodelers and the nuclear pore complex. However, in stark contrast to these pancreatic phenotypes, the SD is entirely dispensable for the development of NKX2.2-dependent cell types within the CNS. Together, these results reveal a previously undetermined mechanism through which NKX2.2 directs disparate transcriptional programs in the pancreas versus neuroepithelium.