DZIP1 regulates mammalian cardiac valve development through a Cby1‐β‐catenin mechanism

Abstract

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 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. Conclusion 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.

DCHS1, Lix1L, and the Septin Cytoskeleton: Molecular and Developmental Etiology of Mitral Valve Prolapse

“…Occurring around E17.5 in mice, we suggest that this process leads to proper stratification of ECM as observed in leaflets from healthy humans and wildtype mice [30]. This hypothesis is supported by the current study and various mouse models that exhibit leaflet enlargements as early as postnatal day zero [3,[31][32][33][34][35]. In diseased valves, cells are unable to properly stratify the ECM because of genetic and molecular perturbations that engender defective mechano-responses to the imposed tension.…”

“…By preserving structures through glutaraldehyde fixation [52], cytoneme-specific signaling has been observed involving hedgehog dependent on myosin 10 (HH) [53] and WNT regulated by VANGL2 [54]. Both of these findings are interesting, given our recent investigations of valve phenotypes in Dhhand Cby1-deficient mice, which exhibit disruptions in actin and beta-catenin, respectively [32,34]. Additionally, FAT4 and DCHS1 were shown to be targets of GLI zinc finger 2 (GLI2) downstream of HH signaling to regulate villi formation [55] and inhibition of the HH receptor Smoothened (SMO) suppressed increased ECM deposition of cells derived from patients with DCHS1 SNV p.R2330C [21].…”

Genetics and pathophysiology of mitral valve prolapse

“…Experimental findings reveal that myxomatous degeneration may occur through altered developmental pathways that involve both ciliogenesis and β-catenin signaling. Matrix metalloproteases were up-regulated in mitral leaflets with subsequent proteolysis of extra-cellular matrix (ECM) collagen and elastin, and myxomatous phenotype ( 28 ). In addition, a significant reduction in MV primary cilia length has been demonstrated in Dchs1 and FlnA knockout (KO) mice ( 27 ).…”

The Potential of Intertwining Gene Diagnostics and Surgery for Mitral Valve Prolapse

“…Thus, the suppressive activity of DZIP1/CBY1 on beta-catenin, which has been delineated as promoting endothelial-to-mesenchyme transformation, endocardial proliferation, ECM remodeling, and the myxomatous degeneration of valves [41,42], is impeded. This leads to the augmented activation of its target gene MMP2, ultimately promoting the loss of the collagenous ECM matrix and resulting in a myxomatous phenotype in the mitral valve [43]. Notably, a mouse model harboring this variant confirmed the pathogenicity of the DZIP1 mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP [40].…”