Abstract
Homeodomain transcription factor Nkx2.2 is required for the final differentiation of the beta-cells in the pancreas and for the production of insulin. Nkx2.2 is expressed in islet cell precursors during pancreatic development and persists in a subset of mature islet cells including all beta-cells. To understand the mechanisms regulating the expression of Nkx2.2 in these different cell populations, we outlined the structure of the mouse nkx2.2 gene and identified regions that direct cell type-specific expression. The nkx2.2 gene has two noncoding alternative first exons (exons 1a and 1b). In transgenic mice, sequences upstream from exon 1a directed expression predominantly in mature islet cells. Within this exon 1a promoter, cooperative interactions between HNF3 and basic helix-loop-helix factors neurogenin-3 or NeuroD1 binding to adjacent sites played key roles in its islet cell-specific expression. In contrast, sequences upstream from exon 1b restricted expression specifically to islet cell precursors. These studies reveal distinct mechanisms for directing the expression of a key differentiation factor in precursors versus mature islet cells.
Highlights
The development and differentiation of organs such as the pancreas involve sequential modifications in gene expression controlled by a cascade of transcription factors
Exon 1b is located ϳ8 kb upstream from exon 1c and the translation initiation site, and exon 1a is located ϳ0.7 kb farther upstream
The 5Ј-RACE results are not quantitative, the adult islet and TC3 RNA produced predominantly exon 1a-containing products, whereas the pancreatic bud and neural tube RNA produced predominantly exon 1b products, suggesting that transcription initiating from these exons is regulated in a tissue-specific manner
Summary
The development and differentiation of organs such as the pancreas involve sequential modifications in gene expression controlled by a cascade of transcription factors. In these mutants there remains a large population of islet cells that do not produce any of the four endocrine hormones These cells express some -cell markers, such as islet amyloid polypeptide and PDX-1, but lack other. Definitive -cell markers including GLUT2, glucokinase, and the -cell-specific homeodomain factor Nkx6.1. These mice demonstrate that Nkx2.2 is necessary for the final differentiation of -cells. During the peak period for -cell neogenesis, from embryonic day 13.5 to 18.5 [13], Nkx2.2 is expressed in a subset of incompletely differentiated endocrine precursor cells that coexpress the bHLH1 proendocrine transcription factor neurogenin-3 [12, 14]. The mechanisms that control Nkx2.2 expression in these different populations are unknown
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