Major ß cell-specific functions of NKX2.2 are mediated via the NK2-specific domain.
Genes Dev
; 37(11-12): 490-504, 2023 06 01.
Article
in En
| MEDLINE
| ID: mdl-37364986
ABSTRACT
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 ß 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 ß cell precursors into mature, insulin-expressing ß cells, resulting in overt neonatal diabetes. Within the adult ß cell, the SD stimulates ß cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for ß cell function. These irregularities in ß 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Homeodomain Proteins
/
Insulin-Secreting Cells
Language:
En
Journal:
Genes Dev
Journal subject:
BIOLOGIA MOLECULAR
Year:
2023
Type:
Article
Affiliation country:
United States