Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2011; 108(1):185-90. DOI: 10.1073/pnas.1004842108
Source: PubMed


During organogenesis, the final size of mature cell populations depends on their rates of differentiation and expansion. Because transient expression of Neurogenin3 (Neurog3) in progenitor cells in the developing pancreas initiates their differentiation to mature islet cells, we examined the role of Neurog3 in cell cycle control during this process. We found that mitotically active pancreatic progenitor cells in mouse embryos exited the cell cycle after the initiation of Neurog3 expression. Transcriptome analysis demonstrated that the Neurog3-expressing cells dramatically up-regulated the mRNA encoding cyclin-dependent kinase inhibitor 1a (Cdkn1a). In Neurog3 null mice, the islet progenitor cells failed to activate Cdkn1a expression and continued to proliferate, showing that their exit from the cell cycle requires Neurog3. Furthermore, induced transgenic expression of Neurog3 in mouse β-cells in vivo markedly decreased their proliferation, increased Cdkn1a levels, and eventually caused profound hyperglycemia. In contrast, in Cdkn1a null mice, proliferation was incompletely suppressed in the Neurog3-expressing cells. These studies reveal a crucial role for Neurog3 in regulating the cell cycle during the differentiation of islet cells and demonstrate that the subsequent down-regulation of Neurog3 allows the mature islet cell population to expand.

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    • ") (Georgia et al., 2006; Miyatsuka et al., 2011). Multiple transcription factors regulate pancreatic endocrine cell development, and they have interacting and sometimes opposing functions. "
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    ABSTRACT: Insulinoma associated 1 (Insm1) plays an important role in regulating the development of cells in the central and peripheral nervous systems, olfactory epithelium and endocrine pancreas. To better define the role of Insm1 in pancreatic endocrine cell development we generated mice with an Insm1(GFPCre) reporter allele and used them to study Insm1-expressing and null populations. Endocrine progenitor cells lacking Insm1 were less differentiated and exhibited broad defects in hormone production, cell proliferation and cell migration. Embryos lacking Insm1 contained greater amounts of a non-coding Neurog3 mRNA splice variant and had fewer Neurog3/Insm1 co-expressing progenitor cells, suggesting that Insm1 positively regulates Neurog3. Moreover, endocrine progenitor cells that express either high or low levels of Pdx1, and thus may be biased towards the formation of specific cell lineages, exhibited cell type-specific differences in the genes regulated by Insm1. Analysis of the function of Ripply3, an Insm1-regulated gene enriched in the Pdx1-high cell population, revealed that it negatively regulates the proliferation of early endocrine cells. Taken together, these findings indicate that in developing pancreatic endocrine cells Insm1 promotes the transition from a ductal progenitor to a committed endocrine cell by repressing a progenitor cell program and activating genes essential for RNA splicing, cell migration, controlled cellular proliferation, vasculogenesis, extracellular matrix and hormone secretion.
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    • "The above results do not support reactivation of the Ngn3 pathway as a mechanism of generating more β-cells in pregnancy. Instead, the drop in the number of Ngn3-expressing cells and the down-regulation of Ngn3 expression in islets during pregnancy is more consistent with the model proposed by Miyatsuka et al, where high levels of Ngn3 expression was found to keep cells in a state of quiescence while down-regulation of Ngn3 expression is required for cell proliferation [26], [27]. This suggests that during pregnancy, down-regulation of Ngn3 in the islets is a prerequisite for β-cell to enter cell cycle and proliferate. "
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    • "Ngn3, transiently expressed in committed precursors, is essential to their endocrine differentiation [3], [28] and involved in islet formation [48] and β-cell regeneration [33], [42]. Obestatin increased Ngn3 gene expression in MLCs at day 9 and reduced their proliferation, suggesting commitment toward the endocrine fate [31]. "
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