Abstract
All pancreatic endocrine cell types arise from a common endocrine precursor cell population, yet the molecular mechanisms that establish and maintain the unique gene expression programs of each endocrine cell lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells to adopt specific endocrine fates. Here, we show that the transcription factor Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells. Heritable expression of Nkx6.1 in endocrine precursors of mice is sufficient to respecify non-beta endocrine precursors towards the beta cell lineage, while endocrine precursor- or beta cell-specific inactivation of Nkx6.1 converts beta cells to alternative endocrine lineages. Remaining insulin+ cells in conditional Nkx6.1 mutants fail to express the beta cell transcription factors Pdx1 and MafA and ectopically express genes found in non-beta endocrine cells. By showing that Nkx6.1 binds to and represses the alpha cell determinant Arx, we identify Arx as a direct target of Nkx6.1. Moreover, we demonstrate that Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, thus establishing competition between Isl1 and Nkx6.1 as a critical mechanism for determining alpha versus beta cell identity. Our findings establish Nkx6.1 as a beta cell programming factor and demonstrate that repression of alternative lineage programs is a fundamental principle by which beta cells are specified and maintained. Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)–derived insulin+ cells, our study has significant implications for developing cell replacement therapies.
Highlights
Innovative strategies for diabetes therapy aim to replace lost insulin-producing beta cells by reprogramming other cell types or by deriving beta cells from pluripotent cells
Diabetes is a disease caused by the loss or dysfunction of insulin-producing beta cells in the pancreas
We have discovered that a single transcription factor can instruct precursor cells of other endocrine cell types to change their identity and differentiate into beta cells
Summary
Innovative strategies for diabetes therapy aim to replace lost insulin-producing beta cells by reprogramming other cell types or by deriving beta cells from pluripotent cells. Ectopic expression of the transcription factors Pdx, Neurogenin 3 (encoded by the Neurog gene; Ngn3), and MafA has been shown to reprogram pancreatic exocrine acinar cells into beta-like cells [1]. Some success in reprogramming of liver cells into beta cells has been reported after misexpression of Pdx, Ngn, MafA, NeuroD, or Nkx6.1 [2,3,4,5,6]. Loss of beta cell identity and partial conversion of beta cells into other endocrine cell types has recently been identified as an early event marking beta cell failure in diabetes [8]. Little is still known about the factors that control this plasticity
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