Processed Vg1 protein is an axial mesoderm inducer in xenopus

Thomsen, Gerald H.; Melton, Douglas A.

doi:10.1016/0092-8674(93)80045-g

Cited by 395 publications

(194 citation statements)

References 56 publications

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“…Alternatively, the secondary structure of Xlefty, or the inherent protease sensitivity at each site, may differ between oocytes and embryonic tissues, such that CS2 cleavage does not occur in embryonic tissues. A general conclusion from our studies, therefore, despite the numerous reported experiments using Xenopus oocytes to infer the mechanisms regulating the biochemical processing of secreted proproteins (Dale et al, 1989;Thomsen and Melton, 1993;Jones et al, 1996;Cui et al, 1998Cui et al, , 2001Eimon and Harland, 2002;Degnin et al, 2004), is that only embryonic cells should be used for future studies of Xlefty.…”

Section: Cleavage Of Xlefty Is Required To Block Xnr Signaling But Nomentioning

confidence: 76%

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Westmoreland

Takahashi

Wright

2007

Developmental Dynamics

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The Nodal and Nodal-related morphogens are utilized for the specification of distinct cellular identity throughout development by activating discrete target genes in a concentration-dependant manner. Lefty is a principal extracellular antagonist involved in the spatiotemporal regulation of the Nodal morphogen gradient during mesendoderm induction. The Xenopus Lefty proprotein contains a single N-linked glycosylation motif in the mature domain and two potential cleavage sites that would be expected to produce long (Xlefty L ) and short (Xlefty S ) isoforms. Here we demonstrate that both isoforms were secreted from Xenopus oocytes, but that Xlefty L is the only isoform detected when embryonic tissue was analyzed. In mesoderm induction assays, Xlefty L is the functional blocker of Xnr signaling. When secreted from oocytes, vertebrate Lefty molecules were N-linked glycosylated. However, glycan addition was not required to inhibit Xnr signaling and did not influence its movement through the extracellular space. These findings demonstrate that Lefty molecules undergo post-translational modifications and that some of these modifications are required for the Nodal inhibitory function.

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Section: Cleavage Of Xlefty Is Required To Block Xnr Signaling But Nomentioning

confidence: 76%

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Westmoreland

Takahashi

Wright

2007

Developmental Dynamics

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“…In addition to the FGFs and activins, Vg1, a TGFβ family member, has been shown to have potent mesoderm-inducing activity (Thomsen and Melton, 1993). Noggin and some Wnt-related molecules, while not mesoderminducing factors themselves, have a dorsalizing effect on induced mesoderm Smith and Harland, 1992;Sokol and Melton, 1992;Thomsen and Melton, 1993), while Xwnt-8 and BMP4, another TGFβ-related factor, appear to attenuate activins ability to induce mesoderm in animal cap assays Dale et al, 1992;Jones et al, 1992;Sokol and Melton, 1991). It is unlikely that any of these factors acts in isolation.…”

Section: Discussionmentioning

confidence: 99%

Mesoderm induction by activin requires FGF-mediated intracellular signals

LaBonne¹,

Whitman²

1994

Trends in Genetics

101

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We have examined the role of FGF signaling during activin-mediated mesoderm induction in Xenopus. Using dominant inhibitory mutants of FGF signal transducers to disrupt the FGF-signaling pathway at the plasma membrane or in the cytosol prevents animal cap blastomeres from expressing several mesodermal markers in response to exogenous activin. Dominant inhibitory mutants o f the FGF receptor, c-ras or c-raf inhibit the ability of activin to induce molecular markers of both dorsal and ventral mesoderm including Xbra, Mix1 and Xnot. Some transcriptional responses to activin such as goosecoid and Xwnt8 are inhibited less effectively than others, however, suggesting that there may differing requirements for an FGF signal in the responses of mesoderm-specific genes to activin induction. Despite the requirement for this signaling pathway during activin induction, downstream components of this pathway are not activated in response to activin, suggesting that activin does not signal directly through this pathway.

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“…For example, the proprotein of Vg-1 is localized to vegetal blastomeres in Xenopus embryos, and is abundant in vegetal cells, but the processed mature form is not readily produced and secreted (22,23). Interestingly, the fusion of the prodomain of BMP-2 with the mature-domain of Vg-1 has been shown to promote production of mature Vg-1 (24). Thus, the prodomain may determine the rate and efficiency of dimer formation and proteolytic cleavage.…”

Section: Fig 4 Bmp-15mentioning

confidence: 99%

Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

Moore²,

Otsuka³

et al. 2003

Journal of Biological Chemistry

144

136

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Bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9 (GDF-9) are members of the transforming growth factor-␤ superfamily. Both molecules are closely related in their primary structures and share a nearly identical spatiotemporal expression pattern in the oocyte during folliculogenesis in mammals. Here we have established a series of cell lines, which express recombinant BMP-15, GDF-9, or both, and investigated whether they form homodimers and/or heterodimers. We demonstrate the first evidence that both BMP-15 and GDF-9 can form non-covalent homodimers when expressed individually, while when both are coexpressed BMP-15/GDF-9 heterodimers are produced. Interestingly, when GDF-9 and BMP-15 are co-expressed the processing of both proproteins are significantly impaired as compared with that of the singly expressed proproteins, suggesting that the proprotein heterodimer is less susceptible to proteolytic cleavage than the individual homodimers. Since BMP-15 mutant sheep, called Inverdale, exhibit severe defects in ovarian function we have also established stable transformants expressing the mutant BMP-15 (InvBMP-15) alone or together with GDF-9. Although InvBMP-15 was previously predicted to be unable to form homodimers, we show here that it does form non-covalent dimers; however, the processing efficiency of InvBMP-15 proprotein is significantly lower than wild-type BMP-15. Surprisingly, when GDF-9 is co-expressed, the processing and secretion of InvBMP-15 is abolished, and the processing of GDF-9 is also severely impaired, suggesting that the heterodimers of InvBMP-15/GDF-9 proproteins are not susceptible to proteolytic cleavage and thus degrade in the cells. Based on these findings we propose a novel hypothesis that a decrease in GDF-9 secretion may be involved in causing infertility in homozygous Inverdale ewes.

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Processed Vg1 protein is an axial mesoderm inducer in xenopus

Cited by 395 publications

References 56 publications

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Mesoderm induction by activin requires FGF-mediated intracellular signals

Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

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