title: Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes.
abstract: Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7(-/-) mice exhibit tail truncation and kinking with 100% penetrance and ventricular septal defects (VSDs) with ~15% penetrance; Fz2(+/-);Fz7(-/-) mice exhibit VSDs with ~50% penetrance and cleft palate with less than 10% penetrance; and Fz2(-/-);Fz7(-/-) mice exhibit convergent extension defects and mid-gestational lethality with 100% penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MA 21205,  USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Yu
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.forename: Nini
authors.initials: N
authors.lastname: Guo
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D000072261:Dishevelled Proteins; D004285:Dogs; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006345:Heart Septal Defects, Ventricular / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010159:Palate / Q000196:embryology*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D054088:Ventricular Septum / Q000196:embryology* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117380:Celsr1 protein, mouse; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C000606585:Dvl3 protein, mouse; D051157:Frizzled Receptors; C489743:Fzd2 protein, mouse; C492041:Fzd7 protein, mouse; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins