Abstract
In diabetic individuals, the imbalance in glucose homeostasis is caused by loss or dysfunction of insulin-secreting beta-cells of the pancreatic islets. As successful generation of insulin-producing cells in vitro could constitute a cure for diabetes, recent studies have explored the molecular program that underlies beta-cell formation. From these studies, the homeodomain transcription factor NKX6.1 has proven to be a key player. In Nkx6.1 mutants, beta-cell numbers are selectively reduced, while other islet cell types develop normally. However, the molecular events downstream of NKX6.1, as well as the molecular pathways that ensure residual beta-cell formation in the absence of NKX6.1 are largely unknown. Here, we show that the Nkx6.1 paralog, Nkx6.2, is expressed during pancreas development and partially compensates for NKX6.1 function. Surprisingly, our analysis of Nkx6 compound mutant mice revealed a previously unrecognized requirement for NKX6 activity in alpha-cell formation. This finding suggests a more general role for NKX6 factors in endocrine cell differentiation than formerly suggested. Similar to NKX6 factors, the transcription factor MYT1 has recently been shown to regulate alpha- as well as beta-cell development. We demonstrate that expression of Myt1 depends on overall Nkx6 gene dose, and therefore identify Myt1 as a possible downstream target of Nkx6 genes in the endocrine differentiation pathway.
Highlights
The possibility of developing a cell-based therapy for treatment of diabetes mellitus has recently generated interest in identifying the molecular pathways that control development of endocrine cells in the pancreas
The imbalance in glucose homeostasis is caused by loss or dysfunction of insulinsecreting β-cells of the pancreatic islets
We show that the Nkx6.1 paralog, Nkx6.2, is expressed during pancreas development and partially compensates for NKX6.1 function
Summary
The possibility of developing a cell-based therapy for treatment of diabetes mellitus has recently generated interest in identifying the molecular pathways that control development of endocrine cells in the pancreas. Endocrine cells are clustered in the islets of Langerhans, in which a large core of insulin-producing β-cells is surrounded by α-, δ- and PP-cells that produce glucagon, somatostatin and pancreatic polypeptide (PP), respectively Because of their role in the pathogenesis of diabetes mellitus, the mechanisms that underlie formation of β-cells have been studied in most detail. Formation of the mouse pancreas begins at embryonic day (E) 9.5 as separate dorsal and ventral evaginations from the foregut endoderm (Slack, 1995) At this stage, the epithelium contains multipotent progenitors that express the transcription factor PDX1 and have the potential to give rise to all pancreatic lineages, comprising endocrine and exocrine cells, as well as cells of the pancreatic ducts (Gu et al, 2002; Herrera, 2002). The first δ- and PP-cells are found at E15.5 and E18.5, respectively (Pictet and Rutter, 1972; Slack, 1995)
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