| First Author | Guo L | Year | 2021 |
| Journal | Dev Dyn | Volume | 250 |
| Issue | 10 | Pages | 1432-1449 |
| PubMed ID | 33811421 | Mgi Jnum | J:311537 |
| Mgi Id | MGI:6771426 | Doi | 10.1002/dvdy.342 |
| Citation | Guo L, et al. (2021) DZIP1 regulates mammalian cardiac valve development through a Cby1-beta-catenin mechanism. Dev Dyn 250(10):1432-1449 |
| abstractText | BACKGROUND: 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. RESULTS: A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and beta-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 beta-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of beta-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 DZIP1(S24R) variant resulted in reduced DZIP1 and CBY1 stability and increased beta-catenin activities. The beta-catenin target gene, MMP2 was up-regulated in the Dzip1(S14R/+) valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype. CONCLUSION: Dzip1 functions to restrain beta-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear beta-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype. |
