Diversin regulates heart formation and gastrulation movements in development

Abstract

Canonical and noncanonical Wnt signaling regulate crucial events in the development of vertebrates and invertebrates. In this work we show that vertebrate Diversin, a potential orthologue of Drosophila Diego, controls fusion of heart precursors and gastrulation movements in zebrafish embryogenesis. These events are regulated by noncanonical Wnt signaling, which is independent of ␤-catenin. We found that Diversin directly interacts with Dishevelled and that this interaction is necessary and sufficient to mediate signals of the noncanonical Wnt pathway to downstream effectors like Rho family GTPases and Jun N-terminal kinase. The ankyrin repeats of Diversin are required for the interaction with Dishevelled, for the activation of noncanonical Wnt signaling, and for the biological responses. The mutation K446M in the DEP domain of vertebrate Dishevelled, which mimics a classical Drosophila loss of function mutation, prevents functional interaction with Diversin's ankyrin repeats. Diversin also affects planar cell polarity in Drosophila, which is controlled by the noncanonical Wnt signaling pathway. Our data thus demonstrate that Diversin and Dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation.convergence and extension ͉ Dishevelled ͉ embryogenesis ͉ noncanonical Wnt signaling ͉ Rho family GTPases

Cilia and coordination of signaling networks during heart development

“…82,[189][190][191][192][193][194] The Wnt signaling network consists of a highly complex signaling arrangement that traditionally is divided into canonical and non-canonical Wnt signaling. 195 In canonical signaling, the binding of Wnt-ligands to Frizzled (Fz) receptors facilitates stabilization of β-catenin, which mediates transcription of canonical Wnt target genes in cell proliferation and differentiation.…”

“…14,165,200,[207][208][209] As an example, NPHP2/inversin and the structurally related diversin in zebrafish are required for convergence extension movement in vertebrates, and depletion of either result in cardiac defects. 190,208 Together, these aspects suggest that inversin and other NPHPs are implicated in heart development by controlling Wnt signaling, but whether this is coordinated by cardiac primary cilia remains speculative at this point.…”

Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways

“…To further investigate the mechanism behind the observed synergy between Frat and Diversin, we took advantage of a series of Diversin deletion mutants generated by Moeller et al (2006) (Figure 5a)), which allowed us to test the requirement of the Axin2/ conduction-binding domain (CBD) of Diversin for the observed synergy with Frat in activation of the two branches of the Wnt pathway.…”

Wnt Signaling in Polycystic Kidney Disease

“…Containing Nterminal ankyrin repeats, Inversin shares its domain architecture with Diversin, the mammalian homologue of Dgo. Diversin blocks canonical but facilitates noncanonical Wnt signaling (45,46), and both Diversin and Dgo interact with Pk and Stbm, providing evidence for a PCP multiprotein complex (15,43,46). Knockdown of Inversin in zebrafish causes pronephric cysts.…”