Loss of Dact1 Disrupts Planar Cell Polarity Signaling by Altering Dishevelled Activity and Leads to Posterior Malformation in Mice

Abstract

Wnt signaling plays a key role in embryogenesis and cancer development. Dvl (Dishevelled) is a central mediator for both the canonical and noncanonical Wnt pathways. Dact1 (Dapper1, Dpr1), a Dvl interactor, has been shown to negatively modulate Wnt signaling by promoting lysosomal degradation of Dvl. Here we report that Dact1-deficient mice have multiple physiological defects that resemble the human neonate disease congenital caudal regression syndrome, including caudal vertebrae agenesis, anorectal malformation, renal agenesis/dysplasia, fused kidneys, and loss of bladder. These urogenital defects can be traced to impaired hindgut formation starting at embryonic day 8.25. Examination of morphological changes and Wnt target gene expression revealed that the planar cell polarity (PCP) signaling is deregulated, whereas the canonical Wnt/␤-catenin pathway is largely unaffected in mutant embryos. Consistently, the activity of the PCP signal mediators Rho GTPase and c-Jun N-terminal kinase is altered in Dact1 ؊/؊ mouse embryonic fibroblasts. We further observed alterations in the protein level and the cellular distribution of Dvl in the primitive streak of mutant embryos. An increased amount of Dvl2 tends to be accumulated in the cortical regions of the cells, especially at the primitive streak ectoderm close to the posterior endoderm that lately forms the hindgut diverticulum. Together, these data suggest that Dact1 may regulate vertebrate PCP by controlling the level and the cellular localization of Dvl protein.

The Wnt Signaling Antagonist Dapper1 Accelerates Dishevelled2 Degradation via Promoting Its Ubiquitination and Aggregate-induced Autophagy

“…Primary mouse embryonic fibroblast (MEFs) were generated from 13.5 day embryos from Dpr1 Ϫ/Ϫ mattings (18) and were maintained in DMEM with 10% FBS added. For starvation, cells were first washed three times with PBS and cultured in Hanks' balanced salt solution (Invitrogen) for the indicated time.…”

“…and thus inhibit both Dvl-mediated canonical and noncanonical Wnt signaling (17)(18)(19). Recently, we found that Dpr1 can promote autophagy initiation by enhancing the Vps34-Beclin1-Atg14L complex formation, and loss of Dpr1 in the central nervous system results in motor coordination deficiency and accumulation of ubiquitinated proteins (20).…”

Protein Kinase A-mediated 14-3-3 Association Impedes Human Dapper1 to Promote Dishevelled Degradation

“…We have also demonstrated that zebrafish and mouse Dpr2 inhibit transforming growth factor-␤ (TGF-␤)/Nodal signaling by promoting degradation of their type I receptors (25,29). Studies with knock-out mouse models revealed that Dpr2 functions in reepithelialization of skin wounds by attenuating TGF-␤ signaling (30), whereas Dpr1 plays a critical role in PCP signaling during development of mice (31,32). Dpr1 regulates morphogenesis of the primitive streak by controlling Vangl2 activity (31) or modulates PCP signaling in early embryos by controlling the level and the cellular localization of Dvl proteins (32).…”

“…Studies with knock-out mouse models revealed that Dpr2 functions in reepithelialization of skin wounds by attenuating TGF-␤ signaling (30), whereas Dpr1 plays a critical role in PCP signaling during development of mice (31,32). Dpr1 regulates morphogenesis of the primitive streak by controlling Vangl2 activity (31) or modulates PCP signaling in early embryos by controlling the level and the cellular localization of Dvl proteins (32). In addition, Dpr1 and Dpr3 have been reported to be down-regulated in human hepatocellular carcinoma and colorectal cancer, respectively (24,33).…”

SEC14 and Spectrin Domains 1 (Sestd1) and Dapper Antagonist of Catenin 1 (Dact1) Scaffold Proteins Cooperatively Regulate the Van Gogh-like 2 (Vangl2) Four-pass Transmembrane Protein and Planar Cell Polarity (PCP) Pathway during Embryonic Development in Mice

“…3, A-D), that precisely phenocopies the spectrum of birth malformations in Dact1 mutant mice described previously by ourselves and independently by another group (29,31). The amazing correspondence of this otherwise unique phenotypic spectrum in two mouse lines with mutations at separate loci (and also engineered in distinct ES cell lines; see under "Materials and Methods") provides compelling evidence that Sestd1 and Dact1 closely cooperate during development.…”