Dataset Information

PAX6 maintains ? cell identity by repressing genes of alternative islet cell types.

ABSTRACT: Type 2 diabetes is thought to involve a compromised ? cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult ? cell identity and function. PAX6 was downregulated in ? cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in ? cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of ? cell function and expansion of ? cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of ? cell genes, thus maintaining mature ? cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human ? cells. We conclude that reduced expression of PAX6 in metabolically stressed ? cells may contribute to ? cell failure and ? cell dysfunction in diabetes.

SUBMITTER: Swisa A

PROVIDER: S-EPMC5199694 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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PAX6 maintains β cell identity by repressing genes of alternative islet cell types.

Swisa Avital A Avrahami Dana D Eden Noa N Zhang Jia J Feleke Eseye E Dahan Tehila T Cohen-Tayar Yamit Y Stolovich-Rain Miri M Kaestner Klaus H KH Glaser Benjamin B Ashery-Padan Ruth R Dor Yuval Y

The Journal of clinical investigation 20161212 1

Type 2 diabetes is thought to involve a compromised β cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult β cell identity and function. PAX6 was downregulated in β cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in β cells of adult mice led to lethal hyperglycemia and ketosis that were at ...[more]

PMID: 27941241

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Project description:Striatal projection neurons comprise two populations of striatonigral and striatopallidal neurons. These two neuronal populations play distinct roles in controlling movement-related functions in the basal ganglia circuits. An important issue is how striatal progenitors are developmentally specified into these two distinct neuronal populations. In the present study, we characterized the function of Islet-1 (Isl1), a LIM-homeodomain transcription factor, in striatal development. Genetic fate mapping showed that Isl1(+) progeny specifically developed into a subpopulation of striatonigral neurons that transiently expressed Isl1. In Nestin-Cre;Isl1(f/f) KO mouse brain, differentiation of striatonigral neurons was defective, as evidenced by decreased expression of striatonigral-enriched genes, including substance P, prodynorphin, solute carrier family 35, member D3 (Slc35d3), and PlexinD1. Striatonigral axonal projections were also impaired, and abnormal apoptosis was observed in Isl1 KO striatum. It was of particular interest that striatopallidal-enriched genes, including dopamine D2 receptor (Drd2), proenkephalin, A2A adenosine receptor (A2aR) and G protein-coupled receptor 6 (Gpr6), were concomitantly up-regulated in Isl1 mutant striatum, suggesting derepression of striatopallidal genes in striatonigral neurons in the absence of Isl1. The suppression of striatopallidal genes by Isl1 was further examined by overexpression of Isl1 in the striatum of Drd2-EGFP transgenic mice using in utero electroporation. Ectopic Isl1 expression was sufficient to repress Drd2-EGFP signals in striatopallidal neurons. Taken together, our study suggests that Isl1 specifies the cell fate of striatonigral neurons not only by orchestrating survival, differentiation, and axonal projections of striatonigral neurons but also by suppressing striatopallidal-enriched genes. The dual action of developmental control by Isl1 in promoting appropriate striatonigral but repressing inappropriate striatopallidal genetic profiles may ensure sharpening of the striatonigral identity during development.

Dataset Information

PAX6 maintains ? cell identity by repressing genes of alternative islet cell types.

Publications

PAX6 maintains β cell identity by repressing genes of alternative islet cell types.

Similar Datasets

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