Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Abstract

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.T he mature structure of an organ depends on its constituent cell populations and how those populations expand and organize as the organ grows. Within the pancreas, the size of the islets of Langerhans and especially how many insulin-producing β-cells they contain is a critical determinant of pancreatic function and the risk of developing diabetes. The number of islet cells depends on the rate at which new endocrine cells [α-, β-, δ-, ε-, and pancreatic polypeptide (PP) cells] differentiate from progenitors, the size of the progenitor population, and the rates of proliferation of the progenitors and mature endocrine cells. Understanding the mechanisms that control these rates will help explain how distinct cell populations assemble into functional organs.The coordinated activity of numerous transcription factors regulates the differentiation of the islet cells (1, 2). Among these factors, Neurogenin3 (Neurog3/Neurog3), a member of the basic helix-loop-helix (bHLH) transcription factor family, transiently marks the progenitor cells that will become islet cells and initiates endocrine differentiation during embryonic development, regeneration, and transdifferentiation (3-10).Although we know that most descendants of Neurog3-expressing cells exit the cell cycle (6, 11), we do not know whether or how Neurog3 might drive cell cycle exit. To address these questions, we used several mouse models with loss-and gain-offunction mutations of Neurog3 and demonstrated that Neurog3 is both necessary and sufficient to promote cellular quiescence in pancreatic progenitors. Furthermore, transcriptome analysis with high time resolution using the Neurog3-Timer mouse model identified the cell...

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

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Postnatal Pancreas of Mice Contains Tripotent Progenitors Capable of Giving Rise to Duct, Acinar, and Endocrine Cells In Vitro

“…+ endocrine progenitors delaminate from the ducts and migrate to form endocrine cells [9,10]. By late gestation (around E18.5), the endocrine cells are loosely arranged as small clusters; at this stage bcells cannot sense glucose and secrete insulin [11,12].…”

Pancreatic Stem Cells: Unresolved Business

“…Although a few studies showed that Ngn3 + cells were proliferative (Jensen et al, 2000;Oliver-Krasinski et al, 2009), the recent genetic clonal analyses of mosaic analysis with double marker (MADM) demonstrated that Ngn3 + cells are quiescent and these cells give rise to a single islet cell type (Desgraz and Herrera, 2009). Consistent with this, a recent seminal study shows that the expression of Ngn3 inhibits proliferation by inducing cyclindependent kinase inhibitor 1a (Cdkn1a) (Miyatsuka et al, 2011). Our recent study demonstrate that in addition to induction of Cdkn1a, numerous genes involved in cell-cycle and cellproliferation are down-regulated (95/127 or 74.8%) (Figure 3) (Jiang et al, 2010).…”