Inhibition of Activin Signaling Induces Pancreatic Epithelial Cell Expansion and Diminishes Terminal Differentiation of Pancreatic β-Cells
You-Qing ZhangMary Malo ClearyYingjie SiGuoxun LiuYuzuru EtoMarcie KritzikSandrine DabernatAyse G. KayaliNora Sarvetnick
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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 β-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.Keywords:
Follistatin
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Pancreatic Islets
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Developmental Biology
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We have previously demonstrated that activin is likely an ovarian mediator of pituitary gonadotropin(s) and local epidermal growth factor in their stimulating oocyte maturation and maturational competence in the zebrafish. However, the downstream events controlled by activin remain unknown. One possible mechanism is that activin may directly work on the oocytes to promote the development of oocyte maturational competence. To substantiate this hypothesis, we performed the present study to demonstrate the expression of the activin system in different compartments of zebrafish follicles, namely, the follicle cells and oocytes. The proteins examined include activin subunits (βA and βB), activin-binding protein (follistatin), activin type II receptors (type IIA and IIB), the type I activin receptor-like kinases (ALK1-like, ALK2-like, and ALK4-like), and the intracellular activin signaling molecules (Smad2, Smad3, Smad4, and Smad7). The results showed that the entire activin signaling system is expressed by the full-grown immature zebrafish oocytes (∼0.65 mm in diameter), including ALK4-like (ActRIB), ALK2-like (ActRIA), ActRIIA, ActRIIB, Smad2, Smad3, Smad4, and Smad7, therefore supporting our hypothesis that the oocytes are one of the direct targets of activin actions in the zebrafish ovary. In contrast, activin itself (βA and βB) and ALK1-like type I receptor are predominantly expressed in the follicle cells surrounding the oocytes. Interestingly, although follistatin is expressed in both the follicle cells and oocytes, its level of expression is significantly higher in the oocytes than the follicle cells, implying that follistatin may serve as a signal from the oocytes to modulate the activity of activin produced by the follicle cells. Taken together, the present study provides convincing evidence that although all members of the activin system are expressed in the whole follicle, they exhibit distinct spatial patterns of expression among different compartments of the follicle. It is likely that activin works directly on the oocytes in a paracrine manner to promote oocyte maturation and maturational competence. On the other hand, instead of being controlled passively by the follicle cells, the oocytes may actively participate in the regulation of follicle development by releasing various modulating molecules such as follistatin.
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Abstract —Activin is a member of the transforming growth factor-β superfamily, and it modulates the proliferation and differentiation of various target cells. In this study, we investigated the role of activin in the initiation and progression of human atherosclerosis. The expression of activin, its physiological inhibitor follistatin, and activin receptors were assayed in human vascular tissue specimens that represented various stages of atherogenesis. In situ hybridization experiments revealed activin mRNA in endothelial cells and macrophages and a strong induction of activin expression in neointimal smooth muscle cells from the early onset of atherogenesis. We developed an “in situ free-activin binding assay” by using biotinylated follistatin, which allowed us to detect bioactive activin at specific sites in atherosclerotic lesions. The mRNAs encoding the activin receptors are expressed similarly in normal and atherosclerotic tissue, which indicates that activin-A signaling in atherogenesis is most likely dependent on changes in growth factor concentrations rather than on receptor levels. In vitro, activin induces the contractile, nonproliferative phenotype in cultured smooth muscle cells, as is reflected by increased expression of smooth muscle-specific markers (SMα-actin and SM22α). Our data provide evidence that activin induces redifferentiation of neointimal smooth muscle cells, and we hypothesize that activin is involved in plaque stabilization.
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Activin and inhibin, members of transforming growth factor-β (TGFβ) superfamily, have diverse and widespread effects within living organisms at many stages during growth and development. From the initial isolation of these growth factors based on their effects of FSH secretion, the study of these factors, as well as of the activin-binding protein follistatin, has progressed from the localization of the expression of the inhibin α subunit, activin βA and βB subunits, and activin receptors in the tissues of various organisms to the examination of activin and inhibin as autocrine and paracrine agents in cell proliferation and differentiation. The inhibitory effects on cell growth and differentiation that have been observed upon treatment of cells with activin suggest that further understanding of the bioactivity of this molecule and its characterization on a molecular level may aid in a more complete understanding of cell growth and differentiation. This minireview discusses the roles of activin, inhibin, and follistatin in the arenas of cell proliferation, differentiation, and embryogenesis, as well as the roles of these molecules in cancerous cells.
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Activin, a member of the transforming growth factor- superfamily of growth and differentiation factors, has a number of actions in embryonic as well as adult tissues.These actions are mediated via a family of receptors containing two subtypes and at least two members of each subtype.Recent evidence demonstrates that activin-responsive cell lines containing different subsets of these receptors are valuable models for dissecting functional relationships among receptor subtype, signal transduced, and response obtained.TT cells, derived from a p53 Ϫ/Ϫ /␣-inhibin Ϫ/Ϫ mouse testicular tumor, respond to activin by proliferating, a response that can be inhibited by follistatin (FS) treatment.Using semiquantitative RT-PCR methods, we characterized steady state messenger RNA (mRNA) levels for the inhibin/activin subunits, FS, and activin receptor subtypes under basal conditions and in the presence of activin or FS.
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There is increasing evidence that activin may act as an autocrine/paracrine regulator of ovarian functions. Activin subunit mRNAs as well as activin immunoreactivities have been detected in the human ovary. Activin alters granulosa cell proliferation and steroidogenesis. The effect of activin is most likely mediated through specific receptors as mRNAs encoding several forms of activin receptors, namely ActR-I, ActR-IB, ActR-II and ActR-IIB are found in the preovulatory follicles as well as in cultured granulosa-luteal cells. Activin-binding protein, follistatin (FS), is also produced in the human ovary. In addition to neutralizing the effect of activin on steroid production, FS on its own also enhances estradiol production, an effect similar to that seen after activin treatment. These findings strongly suggest that activin and FS are important local regulators of steroidogenesis in the human ovary.
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