Sustained
            <i>Neurog3</i>
            expression in hormone-expressing islet cells is required for endocrine maturation and function

Wang, Sui; Jensen, Jan; Seymour, Philip A.; Hsu, Wei-Hsuan; Dor, Yuval; Sander, Maike; Magnuson, Mark A.; Serup, Palle; Gu, Guoqiang

doi:10.1073/pnas.0904247106

Cited by 147 publications

(165 citation statements)

References 33 publications

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“…Interestingly, however, a very low level of Neurog3 expression persists in adult islets (30)(31)(32)(33). Recent studies demonstrated that this sustained low-level expression of Neurog3 contributes to endocrine function (33). Considering these data together, we conclude that sustained, but tightly regulated, expression of Neurog3 at a very low level permits the proper expansion of endocrine cells as well as their normal function.…”

Section: Discussionmentioning

confidence: 59%

“…Our data demonstrate that without normal down-regulation of Neurog3, the β-cell population does not adequately expand and diabetes ensues. Interestingly, however, a very low level of Neurog3 expression persists in adult islets (30)(31)(32)(33). Recent studies demonstrated that this sustained low-level expression of Neurog3 contributes to endocrine function (33).…”

Section: Discussionmentioning

confidence: 99%

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Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Miyatsuka

Kosaka

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

105

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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...

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Miyatsuka

Kosaka

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

105

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“…Subsequently, the presence of NEUROG3 protein has been confirmed by others and its role in the maintenance of adult beta cell maturity was suggested [43]. It is possible that activin and follistatin have reciprocal effects on NEUROG3 levels in beta cells, but it remains to be determined whether NEUROG3 mediates the effects of activin or follistatin on key beta cell genes such as Mafa and Glut2.…”

Section: Discussionmentioning

confidence: 93%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.

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“…Endocrine cell differentiation requires loss of NOTCH signalling and binding of a number of transcription factors to the Neurog3 promoter including: one cut homeobox 1 (ONECUT1), SOX9, hepatocyte nuclear factor 1β (HNF1B), forkhead box protein A2 (FOXA2) and NEUROG3 itself [15,42,54,[56][57][58]. This study adds to the cadre of factors that regulate NEUROG3 by demonstrating that SOX4 participates in this NEUROG3 regulatory network.…”

Section: Sox4 Regulates Factors Downstream Of Neurog3mentioning

confidence: 99%

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

Krentz

Tan

et al. 2015

Diabetologia

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Aims/hypothesis The sex-determining region Y (SRY)-related high mobility group (HMG) box (SOX) family of transcription factors is essential for normal organismal development. Despite the longstanding knowledge that many SOX family members are expressed during pancreas development, a role for many of these factors in the establishment of insulinproducing beta cell fate remains to be determined. The aim of this study is to elucidate the role of SOX4 during beta cell development. Methods We used pancreas and endocrine progenitor mouse knockouts of Sox4 to uncover the roles of SOX4 during pancreas development. Lineage tracing and in vitro models were used to determine how SOX4 regulates beta cell formation and understand the fate of Sox4-null endocrine lineage cells. Results This study demonstrates a progenitor cellautonomous role for SOX4 in regulating the genesis of beta cells and shows that it is required at multiple stages of the process. SOX4 deletion in the multipotent pancreatic progenitors resulted in impaired endocrine progenitor cell differentiation. Deletion of SOX4 later in the Neurog3-expressing cells also caused reductions in beta cells. Lineage studies showed loss of Sox4 in endocrine progenitors resulted in a block in terminal islet cell differentiation that was attributed to reduction in the production of key beta cell specification factors. Conclusions/interpretation These results demonstrate that SOX4 is essential for normal endocrine pancreas development both concomitant with, and downstream of, the endocrine fate decision. In conclusion, these studies position Sox4 temporally in the endocrine differentiation programme and provide a new target for improving in vitro differentiation of glucoseresponsive pancreatic beta cells.

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Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function

Cited by 147 publications

References 33 publications

Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

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