%0 Journal Article
%T DZIP1 regulates mammalian cardiac valve development through a Cby1-β-catenin mechanism.
%A Guo L
%A Beck T
%A Fulmer D
%A Ramos-Ortiz S
%A Glover J
%A Wang C
%A Moore K
%A Gensemer C
%A Morningstar J
%A Moore R
%A Schott JJ
%A Le Tourneau T
%A Koren N
%A Norris RA
%J Dev Dyn
%V 250
%N 10
%D Oct 2021
%M 33811421
%F 2.842
%R 10.1002/dvdy.342
%X <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.