Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection

Maldonado, Thomas S.; Kadison, Alan S.; Crisera, Christopher A.; Grau, Juan B.; Alkasab, Susan L.; Longaker, Michael T.; Gittes, George K.

doi:10.1016/s1091-255x(00)80075-x

Cited by 39 publications

(23 citation statements)

References 34 publications

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“…Because activins and their receptors promote the differentiation processes, we investigated whether the natural activin inhibitors were present during pancreatic differentiation. In NOD mice, follistatin expression was found inside the islets, consistent with previous reports (6,22). In the regenerating pancreas, follistatin immunoreactivity was in the islet-like clusters and in a subpopulation of the ductal cells in large ducts (Fig.…”

Section: Expression Of Activins and Their Receptors During Pancreaticsupporting

confidence: 92%

“…Interestingly, activin receptors are expressed in the primordia of foregut organs including pancreas, stomach, intestine, and lung (4), and activins are expressed in the pancreatic bud during development (5,6). Transgenic mice that express a dominant-negative mutation of activin type II receptors (7,8) or mice deficient for activin receptors (9) display reduced levels of differentiated islet cells.…”

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confidence: 99%

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

Zhang

Cleary

et al. 2004

Diabetes

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Activins regulate the growth and differentiation of a variety of cells. During pancreatic islet development, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. In this study, we probed the role of activin signaling during pancreatic islet cell development and regeneration. Indeed, we found that both activins and activin receptors are upregulated in duct epithelial cells during islet differentiation. Interestingly, the expression of endogenous cellular inhibitors of activin signaling, follistatin and Cripto, were also found to be augmented. Inhibition of activins significantly enhanced survival and expansion of pancreatic epithelial cells but decreased the numbers of differentiated ␤-cells. Our results suggest that the homeostasis of growth and terminal differentiation requires a precise context-dependent regulation of activin signaling. Follistatin participates in this process by promoting expansion of precursor cells during pancreas growth.

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Section: Expression Of Activins and Their Receptors During Pancreaticsupporting

confidence: 92%

mentioning

confidence: 99%

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

Zhang

Cleary

et al. 2004

Diabetes

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“…TGF-βs 1 and 2 are expressed in islets and have been shown to acutely enhance GSIS [4][5][6]. Activins A and B are also expressed in islet cells, suggesting autocrine and/or paracrine roles in islet cell function and glucose homeostasis [7][8][9][10][11]. Immunohistochemical studies have localised activin A predominantly to alpha cells, while activin B was shown to be expressed by both alpha and beta cells [4].…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Mezghenna

Mármol

et al. 2013

Diabetologia

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Aims/hypothesis Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is regulated by paracrine factors, the identity and mechanisms of action of which are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis. Methods We examined glucose homeostatic responses in mice lacking activin B and in pancreatic islets derived from these mutants. We compared the ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and beta cells. Results Mice lacking activin B displayed elevated serum insulin levels and GSIS. Injection of a soluble activin B antagonist phenocopied these changes in wild-type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS, which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild-type islets, while activin A displayed the opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta cells, while Smad2 showed a preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets. Conclusions/interpretation These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta cells, and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease.

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“…Although the importance of activin signaling for pancreas development and ␤-cell differentiation is well established (4,5), much less is known about the physiological functions of activins and related ligands in adult pancreatic islets in vivo. Activins A and -B are expressed in islet cells, suggesting autocrine and/or paracrine roles within islets (6,7). In vitro experiments have indicated an ability of activin A to increase cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i ) and induce insulin secretion in ␤-cells even at very low levels of ambient glucose (8,9).…”

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confidence: 99%

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Bertolino

Holmberg

Reissmann

et al. 2008

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

113

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All major cell types in pancreatic islets express the transforming growth factor (TGF)-␤ superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in ␤-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca 2؉ signaling in islet cells, with activin A increasing, but activin B decreasing, glucosestimulated Ca 2؉ influx. On its own, activin B had no effect on WT cells, but stimulated Ca 2؉ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7 ؊/؊ mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca 2؉ signaling in ␤-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting ␤-cell function by mediating the effects of activin B on Ca 2؉ signaling.T he signaling networks controlling metabolic processes are highly regulated and integrate the actions of both positively and negatively acting components from many different signaling pathways. Members of the transforming growth factor (TGF)-␤ superfamily, including TGF-␤s, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and activins, have been implicated in the regulation of several metabolic processes. These ligands signal via distinct complexes of type I and type II receptor serine-threonine kinases, each binding to different classes of TGF-␤ ligands (1, 2). The main and most widely studied signaling pathway downstream of these receptors involves activation and nuclear translocation of Smad proteins, which in turn regulate gene transcription through multiple interactions with distinct sets of transcription factors in a cell type-specific manner (1, 2). Although less well understood, Smad-independent pathways have also been described in a variety of cell systems and involve the activation of MAP kinases, small GTPases, and Ca 2ϩ mobilization (3).Identification of cell-intrinsic factors controlling the specification and function of pancreatic endocrine cells is of major importance for understanding the regulation of blood-glucose homeostasis. The characterization of signals regul...

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Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection

Cited by 39 publications

References 34 publications

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

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

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

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