Wardle, Fiona Claire; (1998) Regulation of the BMP signalling pathway by BMP1-related metalloproteases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Bone Moiphogenetic Proteins (BMPs) 2-8 are members of the TGFβ superfamily of secreted signalling molecules. During embryonic development BMPs are involved in many processes including cell fate determination, morphogenesis, growth and programmed cell death, all of which are essential for normal development. BMP activity may be regulated in variety of ways. Of particular interest is the finding that three Xenopus proteins. Noggin, Chordin and Follistatin are able to bind BMP4 and prevent it activating its receptor (Piccolo et al., 1996; Zimmerman et al., 1996; Fainsod et al., 1997). Inhibition by Chordin can be alleviated by Xolloid, a BMP1-related metalloprotease that cleaves Chordin (Piccolo et al., 1997). Similarly, in the Drosophila embryo Dpp, a BMP2/4 homologue, is inhibited by the Chordin homologue, Sog, but activated by Tolloid, a BMP 1-related metalloprotease (Marques et al., 1997). Since BMP1-related metalloproteases are present during development of many animal species, an attractive hypothesis is that release from inactive complexes by these metal loproteases is a general mechanism for regulating BMP activity. Mesodermal patterning during Xenopus development, a process known to require BMP activity, is used as a test system to investigate the role of BMP 1-related metalloproteases in BMP signalling. Recent experiments have shown that overexpression of XBMPl and Xolloid partially ventralizes dorsal mesoderm (Goodman et al., 1998). In contrast, expression of the sea urchin BMP 1-related metalloprotease, SpAN, completely ventralizes dorsal mesoderm. This ventralizing activity requires a functional BMP signalling pathway, indicating that these metalloproteases may be activating endogenous BMPs in the Xenopus embryo. In addition, SpAN, XBMP1 and Xolloid inhibit the activity of Chordin and SpAN is also inhibits Noggin. To further test the action of these metalloproteases, putative dominant-negative constructs were made, lacking the metalloprotease domain but retaining the protein-protein interaction domains. These truncated constructs dorsalize ventral mesoderm, consistent with the truncated protein binding its target, but being unable to process it. Finally, two sea urchin TGFβs expressed during early sea urchin development, Univin and suBMP2/4, were tested in the Xenopus embryo and found to be functionally homologous to Vgl and BMP4 respectively, suggesting that similar molecules may act in both sea urchins and Xenopus to pattern the early embryo.

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