The HMG Box Transcription Factor Sox4 Contributes to the Development of the Endocrine Pancreas

Wilson, Melinda E.; Yang, Katherine; Kalousova, Anna; Lau, Janet; Kosaka, Yasuhiro; Lynn, Francis C.; Wang, Juehu; Mrejen, Caroline; Episkopou, Vasso; Clevers, Hans; German, Michael S.

doi:10.2337/diabetes.54.12.3402

Cited by 101 publications

(108 citation statements)

References 58 publications

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“…1B). Of these genes, SOX4/sox4b has been linked to both pancreatic development (16,17) and insulin secretion in the mouse (18), and as such represents a plausible candidate for T2D, whereas cdkal1 in zebrafish is expressed ubiquitously and at low levels (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

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

198

152

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Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes

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Section: Resultsmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

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

198

152

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“…As such, the previous pancreatic studies did not definitively show that cell-autonomous actions of SOX4 in the pancreatic epithelium were necessary [28,31,53]. Furthermore, the early studies did not uncover when SOX4 becomes important for islet cell formation or how it functions to regulate islet cell genesis.…”

Section: Sox4 Regulates Factors Downstream Of Neurog3mentioning

confidence: 78%

“…Null mutation of Sox4 results in cardiac abnormalities, defects in blood flow and embryonic lethality by E14.5 prior to completion of the bulk of endocrine cell differentiation. However, significant reductions of insulin (INS) and/or glucagon (GCG) expression were observed by us and others [29,31].…”

Section: Introductionmentioning

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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“…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%

Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

Miyatsuka

Kosaka

Kim

et al. 2010

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

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117

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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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The HMG Box Transcription Factor Sox4 Contributes to the Development of the Endocrine Pancreas

Cited by 101 publications

References 58 publications

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

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

Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a

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