Skeletogenesis is a complex and poorly understood biological process controlled by a variety of morphogenetic programs and cellular activities. Central to the harmonious formation and growth of the vertebrate skeleton is the proper development of cartilage. This is in turn the result of the correct spatiotemporal expression of several differentiation-specific genes, such as the one encoding the pro-alpha1 subunit of type II collagen. This extracellular glycoprotein is a critical contributor to the structural integrity of cartilaginous tissues, and to the growth and shape of skeletal bone. Type II collagen is also produced by epithelial and mesenchymal cells at pre- and non-chondrogenic sites of the developing vertebrate embryo. This early phase of gene expression is associated with the synthesis of a protein longer than the one made later in development and in the adult organism. The procollagen isoforms are the result of alternative splicing of exon 2 sequence. Exon 2 codes for the cysteine- rich motif of the N-propeptide, a sequence believed to exert a negative feedback control on collagen biosynthesis. The phylogenetic conservation of this tissue- and stage-specific pattern of gene expression strongly suggests a function other than structural for the long isoform of type II procollagen. Accordingly, it has been hypothesized that this macromolecule may be somehow implicated in establishing the subsequent pattern of skeletogenesis. It is the scope of this application to test the validity of this hypothesis using the power of the genetic approach. Toward this end, we propose to analyze the phenotype of transgenic mice expressing only one of the two pro-alpha1(II) collagen isoforms during the entire developmental process. In addition to providing new insights into the role of type II collagen in chondrogenesis, this work will also enhance our understanding of the pathogenesis of disorders that are directly or indirectly connected with the expression of this extracellular macromolecule.
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