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Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells.

ABSTRACT: Recently, loss of beta-cell-specific traits has been proposed as an early cause of beta cell failure in diabetes. However, the molecular mechanisms that underlie the loss of beta cell features remain unclear. Here, we identify an Nkx6.1-controlled gene regulatory network as essential for maintaining the functional and molecular traits of mature beta cells. Conditional Nkx6.1 inactivation in adult mice caused rapid-onset diabetes and hypoinsulinemia. Genome-wide analysis of Nkx6.1-regulated genes and functional assays further revealed a critical role for Nkx6.1 in the control of insulin biosynthesis, insulin secretion, and beta cell proliferation. Over time, Nkx6.1-deficient beta cells acquired molecular characteristics of delta cells, revealing a molecular link between impaired beta cell functional properties and loss of cell identity. Given that Nkx6.1 levels are reduced in human type 2 diabetic beta cells, our study lends support to the concept that loss of beta cell features could contribute to the pathogenesis of diabetes.

SUBMITTER: Taylor BL

PROVIDER: S-EPMC4058003 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells.

Taylor Brandon L BL Liu Fen-Fen FF Sander Maike M

Cell reports 20130912 6

Recently, loss of beta-cell-specific traits has been proposed as an early cause of beta cell failure in diabetes. However, the molecular mechanisms that underlie the loss of beta cell features remain unclear. Here, we identify an Nkx6.1-controlled gene regulatory network as essential for maintaining the functional and molecular traits of mature beta cells. Conditional Nkx6.1 inactivation in adult mice caused rapid-onset diabetes and hypoinsulinemia. Genome-wide analysis of Nkx6.1-regulated genes ...[more]

PMID: 24035389

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Project description:BACKGROUND:The expression of a specific combination of transcription factors (TFs) in the multipotent progenitor cells (MPCs) is critical for determining pancreatic cell fate. NKX6.1 expression in PDX1+ MPCs is required for functional ? cell generation. We have recently demonstrated the generation of a novel population of human pluripotent stem cell (hPSC)-derived MPCs that exclusively express NKX6.1, independently of PDX1 (PDX1-/NKX6.1+). Therefore, the aim of this study was to characterize this novel population to elucidate its role in pancreatic development. METHODS:The hPSCs were exposed to two differentiation protocols to generate MPCs that were analyzed using different techniques. RESULTS:Based on the expression of PDX1 and NKX6.1, we generated three different populations of MPCs, two of them were NKX6.1+. One of these NKX6.1 populations coexpressed PDX1 (PDX1+/NKX6.1+) which is known to mature into functional ? cells, and an additional novel population did not express PDX1 (PDX1-/NKX6.1+) with an undefined role in pancreatic cell fate. This novel population was enriched using our recently established protocol, allowing their reorganization in three-dimensional (3D) structures. Since NKX6.1 induction in MPCs can direct them to endocrine and/or ductal cells in humans, we examined the coexpression of endocrine and ductal markers. We found that the expression of the pancreatic endocrine progenitor markers chromogranin A (CHGA) and neurogenin 3 (NGN3) was not detected in the NKX6.1+ 3D structures, while few structures were positive for NKX2.2, another endocrine progenitor marker, thereby shedding light on the origin of this novel population and its role in pancreatic endocrine development. Furthermore, SOX9 was highly expressed in the 3D structures, but cytokeratin 19, a main ductal marker, was not detected in these structures. CONCLUSIONS:These data support the existence of two independent NKX6.1+ MPC populations during human pancreatic development and the novel PDX1-/NKX6.1+ population may be involved in a unique trajectory to generate ? cells in humans.

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Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells.

Publications

Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells.

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