Inhibition of Activin Signaling Induces Pancreatic Epithelial Cell Expansion and Diminishes Terminal Differentiation of Pancreatic β-Cells

Zhang, You Qing; Cleary, Mary Malo; Si, Yingjie; Liu, Guoxun; Eto, Yuzuru; Kritzik, Marcie; Dabernat, Sandrine; Kayali, Ayse G.; Sarvetnick, Nora

doi:10.2337/diabetes.53.8.2024

Cited by 58 publications

(44 citation statements)

References 45 publications

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“…Together, our data show that GDF11 activity regulates both the production of pancreatic islet progenitor cells and the maturation of these progenitor cells into insulin-producing β-cells. Further support for this view also comes from a recent study by Sarvetnick and colleagues, who show that TGF-β signaling may regulate endocrine cell maturation in the postnatal pancreas (Zhang et al, 2004). Future studies should allow us to determine whether GDF11 and SMAD2 signaling also serve to maintain the function and fate of fully differentiated endocrine cells in the adult pancreas.…”

Section: Gdf11 and Smad2 Activity Regulate Pancreatic β-Cell Maturatimentioning

confidence: 65%

GDF11 modulates NGN3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development

et al. 2004

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Identification of endogenous signals that regulate expansion and maturation of organ-specific progenitor cells is a major goal in studies of organ development. Here we provide evidence that growth differentiation factor 11(GDF11), a member of the TGF-β ligand family, governs the number and maturation of islet progenitor cells in mouse pancreas development. Gdf11 is expressed in embryonic pancreatic epithelium during formation of islet progenitor cells that express neurogenin 3. Mice deficient for Gdf11 harbor increased numbers of NGN3+ cells,revealing that GDF11 negatively regulates production of islet progenitor cells. Despite a marked expansion of these NGN3+ islet progenitors, mice lacking Gdf11 have reduced β-cell numbers and evidence of arrested β-cell development, indicating that GDF11 is also required for β-cell maturation. Similar precursor and islet cell phenotypes are observed in mice deficient for SMAD2, an intracellular signaling factor activated by TGF-β signals. Our data suggest that Gdf11 and Smad2 regulate islet cell differentiation in parallel to the Notch pathway, which previously has been shown to control development of NGN3+ cells. Thus, our studies reveal mechanisms by which GDF11 regulates the production and maturation of islet progenitor cells in pancreas development.

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Section: Gdf11 and Smad2 Activity Regulate Pancreatic β-Cell Maturatimentioning

confidence: 65%

GDF11 modulates NGN3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development

et al. 2004

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“…Although adipose tissue is the most prominent site of GDF3 expression, this ligand has also been detected in circulation in the bloodstream (9) and may thus affect fat deposition and energy balance through non-cell-autonomous effects. The requirement for the Cripto coreceptor, which is excluded from several tissues that express other GDF3 receptor components-such as pancreatic ␤-cells (24), is likely to provide tissue specificity to GDF3 signaling. Future studies, including conditional inactivation, will be required to unravel tissue-specific effects of GDF3 and its receptors.…”

Section: Discussionmentioning

confidence: 99%

Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity

Andersson

Korach-André

Reissmann

et al. 2008

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

116

139

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Growth/differentiation factor 3 (GDF3) is highly expressed in adipose tissue, and previous overexpression experiments in mice have suggested that it may act as an adipogenic factor under conditions of high lipid load. GDF3 has been shown to signal via the activin receptor ALK4 during embryogenesis, but functional receptors in adipose tissue are unknown. In this study, we show that Gdf3 ؊/؊ mutant mice accumulate less adipose tissue than WT animals and show partial resistance to high-fat diet-induced obesity despite similar food intake. We also demonstrate that GDF3 can signal via the ALK4-homolog ALK7 and the coreceptor Cripto, both of which are expressed in adipose tissue. In agreement with a role for ALK7 in GDF3 signaling in vivo, mutant mice lacking ALK7 also showed reduced fat accumulation and partial resistance to diet-induced obesity. We propose that GDF3 regulates adiposetissue homeostasis and energy balance under nutrient overload in part by signaling through the ALK7 receptor.high-fat diet ͉ metabolism ͉ TGF-␤ ͉ energy balance ͉ insulinemia

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“…Activins control embryonic patterning of foregut-derived organs [19], have important roles in pancreatic development [20] and have been implicated in the control of insulin secretion [21,22]. Activins and their receptors are present in the developing pancreas and adult islet cells [23,24].…”

Section: Introductionmentioning

confidence: 99%

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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Inhibition of Activin Signaling Induces Pancreatic Epithelial Cell Expansion and Diminishes Terminal Differentiation of Pancreatic β-Cells

Cited by 58 publications

References 45 publications

GDF11 modulates NGN3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development

GDF11 modulates NGN3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development

Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity

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

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