Follistatin Regulates Bone Morphogenetic Protein-7 (BMP-7) Activity to Stimulate Embryonic Muscle Growth

Amthor, Helge; Christ, Bodo; Rashid‐Doubell, Fiza; Kemp, C. Fred; Lang, Emily; Patel, Ketan

doi:10.1006/dbio.2001.0555

Cited by 120 publications

(100 citation statements)

References 44 publications

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“…1B). Follistatin is a well characterized antagonist of Activin signaling that can antagonize BMP signaling in some systems (43,44) but not others (45). To determine if the low level of Follistatin expression in ES cells modulates BMP signaling in mouse ES cells, follistatin levels were reduced via siRNA transfection, and Id1 expression was examined to measure BMP-Smad1/5 activity.…”

Section: Manipulation Of Smad7 Levels Alters Sb431542-mediated Phosphmentioning

confidence: 99%

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

Galvin

Travis

Yee

et al. 2010

Journal of Biological Chemistry

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Members of the transforming growth factor-␤ superfamily play essential roles in both the pluripotency and differentiation of embryonic stem (ES) cells. Although bone morphogenic proteins (BMPs) maintain pluripotency of undifferentiated mouse ES cells, the role of autocrine Nodal signaling is less clear. Pharmacological, molecular, and genetic methods were used to further understand the roles and potential interactions of these pathways. Treatment of undifferentiated ES cells with SB431542, a pharmacological inhibitor of Smad2 signaling, resulted in a rapid reduction of phosphorylated Smad2 and altered the expression of several putative downstream targets. Unexpectedly, inhibition of the Nodal signaling pathway resulted in enhanced BMP signaling, as assessed by Smad1/5 phosphorylation. SB431542-treated cells also demonstrated significant induction of the Id genes, which are known direct targets of BMP signaling and important factors in ES cell pluripotency. Inhibition of BMP signaling decreased the SB431542-mediated phosphorylation of Smad1/5 and induction of Id genes, suggesting that BMP signaling is necessary for some Smad2-mediated activity. Because Smad7, a known inhibitory factor to both Nodal and BMP signaling, was down-regulated following inhibition of Nodal-Smad2 signaling, the contribution of Smad7 to the cross-talk between the transforming growth factor-␤ pathways in ES cells was examined. Biochemical manipulation of Smad7 expression, through shRNA knockdown or inducible gene expression, significantly reduced the SB431542-mediated phosphorylation of Smad1/5 and induction of the Id genes. We conclude that autocrine Nodal signaling in undifferentiated mouse ES cells modulates the vital pluripotency pathway of BMP signaling. Mouse embryonic stem (ES)2 cells are derived from the inner cell mass of the early blastocyst. It is from the inner cell mass that the germ layers arise to produce all cell types of the adult. The capacity of ES cells to either self-renew or differentiate into cells of the three germ layers provides an excellent tool for studying early embryonic development, including self-renewal and pluripotency (1). Some of the essential factors controlling ES cell pluripotency have been identified; however, additional work is necessary to identify other functional signaling pathways that impinge upon the ES cell phenotype, to determine genes that are regulated by these pathways, and to discover how the various pathways interact. Applications of this work will yield insights into the promising use of stem cells for regenerative therapies.ES cells can be maintained as pluripotent cells when grown on mitotically inactivated embryonic fibroblasts or when grown in media supplemented with leukemia inhibitory factor (LIF (2, 3)). Additionally, under serum-free culture conditions, signaling through the bone morphogenetic protein (BMP) pathway is essential for maintaining mouse ES cell pluripotency (4, 5). The combination of LIF and BMP4 inhibits multiple differentiation-inductive signals, a capability that...

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Section: Manipulation Of Smad7 Levels Alters Sb431542-mediated Phosphmentioning

confidence: 99%

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

Galvin

Travis

Yee

et al. 2010

Journal of Biological Chemistry

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“…These genes were also strongly expressed in C2C12 cells, but displayed only low levels in SM tissue. By compiling sets of genes that vary significantly in their mean relative expression between the two RMS subtypes (Tables 2 and 3), we detected several genes previously associated with rhabdomyosarcomagenesis or myogenic differentiation, namely Fos (Fleischmann et al, 2003), myogenic differentiation 1 (MyoD1) (Kablar et al, 2003), Junb (Chalaux et al, 1998), follistatin (Amthor et al, 2002;Armand et al, 2003), heparin binding epidermal growth factor-like growth factor (Chen et al, 1995), matrix metalloproteinase 9 (Kherif et al, 1999) and p21 cip1/waf1 (see Figure 4b). These genes generally displayed higher transcript levels in Ptch1-dependend RMS than in p53-dependend RMS (Table 2).…”

Section: Ptch1-and P53-dependent Rms Differ Extremely In the Time Of mentioning

confidence: 99%

Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

et al. 2004

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Rhabdomyosarcoma (RMS) is a highly malignant tumor that is histologically related to skeletal muscle, yet genetic and molecular lesions underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of two different mouse models of RMS, each associated with a defined primary genetic defect known to play a role in rhabdomyosarcomagenesis in man. We report that RMS of heterozygous Patched1 (Ptch1) mice show less aggressive growth and a greater degree of differentiation than RMS of heterozygous p53 mice. By means of cDNA microarray analysis we demonstrate that RMS in Ptch1 mutants predominantly express a number of myogenic markers, including myogenic differentiation 1, myosin heavy chain, actin, troponin and tropomyosin, as well as genes associated with Hedgehog/Patched signaling like insulin-like growth factor 2, forkhead box gene Foxf1 and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp contrast, RMS in p53 mutants display higher expression levels of cell cycle-associated genes like cyclin B1, cyclindependent kinase 4 and the proliferation marker Ki-67. These results demonstrate that different causative mutations lead to distinct gene expression profiles in RMS, which appear to reflect their different biological characteristics. Our results provide a first step towards a molecular classification of different forms of RMS. If the described differences can be confirmed in human RMS our results will contribute to a new molecular taxonomy of this cancer, which will be critical for gene mutation-and expression-specific therapy.

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“…Follistatin also inhibits the effects of OP-1 (also known as BMP-7), if added at a 10-fold excess (Yamashita et al, 1995). During the development of chick limbs, follistatin promotes the ability of BMP-7 to induce muscle growth but inhibits the ability of BMP-7 to induce apoptosis and muscle loss by flexible and reversible binding to BMP-7 (Amthor et al, 2002). Iemura et al (1998) demonstrated that in the early Xenopus embryo follistatin can inhibit the effects of BMP-2, -4 and -7 by direct binding to a complex of BMP and its receptor.…”

Section: Function Of Follistatin As a Binding Proteinmentioning

confidence: 99%

Regulation of ovarian function by the TGF-beta superfamily and follistatin

et al. 2003

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The role of follistatin as an activin-binding protein has dominated the study of this molecule for the last 10 years. However, there is emerging evidence that follistatin has a role in modulating the biology of other members of the transforming growth factor beta (TGF-beta) superfamily. This review summarizes the current concepts encompassing follistatin biochemistry as well as molecules with which it is functionally associated. Moreover, the importance of the two follistatin isoforms (follistatin-288 and follistatin-315) is discussed with particular emphasis on the regulation of the ovary. In addition to activin, this review discusses the functions of other members of the TGF-beta superfamily, for example growth differentiation factor 9 (GDF-9), bone morphogenetic protein 15 (BMP-15), BMP-6, BMP-4 and BMP-7, in the ovary, and the potential interactions between follistatin and these growth factors. The complex network of TGF-beta superfamily growth factor members involved in the modulation of ovarian function and the interactions of follistatin with these proteins is highlighted.

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Follistatin Regulates Bone Morphogenetic Protein-7 (BMP-7) Activity to Stimulate Embryonic Muscle Growth

Cited by 120 publications

References 44 publications

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

Regulation of ovarian function by the TGF-beta superfamily and follistatin

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