{Reference Type}: Journal Article
{Title}: DZIP1 regulates mammalian cardiac valve development through a Cby1-β-catenin mechanism.
{Author}: Guo L;Beck T;Fulmer D;Ramos-Ortiz S;Glover J;Wang C;Moore K;Gensemer C;Morningstar J;Moore R;Schott JJ;Le Tourneau T;Koren N;Norris RA;
{Journal}: Dev Dyn
{Volume}: 250
{Issue}: 10
{Year}: Oct 2021
{Factor}: 2.842
{DOI}: 10.1002/dvdy.342
{Abstract}: <B>BACKGROUND: </B>Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood.<BR><B>RESULTS: </B>A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and β-catenin. Co-expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of β-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of β-catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non-syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased β-catenin activities. The β-catenin target gene, MMP2 was up-regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype.<BR><B>CONCLUSIONS: </B>Dzip1 functions to restrain β-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear β-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.