Abstract
<h3>Abstract</h3> The extracellular matrix (ECM) undergoes an orchestrated transition from embryonic to mature ECM that is essential for postnatal life, yet the developmental transition mechanisms for ECM components and macromolecular complexes are poorly defined. Fibrillin microfibrils are macromolecular ECM complexes with important structural and regulatory roles. In mice, <i>Fbn1</i> and <i>Fbn2</i> mRNAs, which encode the major microfibrillar components, are strongly expressed during embryogenesis. <i>Fbn2</i> mRNA levels rapidly decline postnatally, consistent with fibrillin-1 being the major component of adult tissue microfibrils. Here, by combining transgenic and N-terminomics strategies with in vitro analysis of microfibril assembly and intermolecular interactions, we identify cooperative proteolysis of fibrillin-2 by the secreted metalloproteases ADAMTS6 and ADAMTS10 as a mechanism contributing to postnatal fibrillin-1 dominance. The primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by demonstrating a dramatic reversal of skeletal defects in <i>Adamts6</i><sup>−/−</sup> embryos by <i>Fbn2</i> haploinsufficiency.
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