FAILURE OF VENTRAL BODY-WALL CLOSURE IN MOUSE EMBRYOS LACKING A PROCOLLAGEN C-PROTEINASE ENCODED BY BMP1, A MAMMALIAN GENE-RELATED TO DROSOPHILA TOLLOID

The mouse bone morphogenetic protein1 (Bmp1) gene encodes a secreted a stacin metalloprotease that cleaves the COOH-propeptide of procollagen I, II and III. BMP-1 is also related to the product of the Drosophila patterning gene, tolloid (tld), which enhances the activity of the TG F beta-related growth factor Decapentaplegic and promotes development of the dorsalmost amnioserosa. We have disrupted the mouse Bmp1 gene b y deleting DNA sequences encoding the active site of the astacin-like protease domain common to all splice variants, Homozygous mutant embry os appear to have a normal skeleton, apart from reduced ossification o f certain skull bones, However, they have a persistent herniation of t he gut in the umbilical region and do not survive beyond birth. Analys is of the amnion of homozygous mutant embryos reveals the absence of t he fold that normally tightly encloses the physiological hernia of the gut. At the electron microscopic level, the extracellular matrix of t he amnion contains collagen fibrils with an abnormal morphology, consi stent with the incorporation of partially processed procollagen molecu les. Metabolical labelling and immunofluorescence studies also reveal abnormal processing and deposition of procollagen by homozygous mutant fibroblasts in culture.