title: PTK7 recruits dsh to regulate neural crest migration.
abstract: PTK7 regulates planar cell polarity (PCP) signaling during vertebrate neural tube closure and establishment of inner ear hair cell polarity; however, its signaling mechanism is unknown. Here, we demonstrate a new function for PTK7 in Xenopus neural crest migration and use this system in combination with in vitro assays to define the intersection of PTK7 with the non-canonical Wnt signaling pathway that regulates PCP. In vitro, using Xenopus ectodermal explants, we show that PTK7 recruits dishevelled (dsh) to the plasma membrane, a function that is dependent on the PDZ domain of dsh, as well as on the conserved kinase domain of PTK7. Furthermore, endogenous PTK7 is required for frizzled7-mediated dsh localization. Immunoprecipitation experiments confirm that PTK7 can be found in a complex with dsh and frizzled7, suggesting that it cooperates with frizzled to localize dsh. To evaluate the in vivo relevance of the PTK7-mediated dsh localization, we analyzed Xenopus neural crest migration, as loss-of-function of PTK7 inhibits neural crest migration in whole embryos as well as in transplanted neural crest cells. Supporting the in vivo role of PTK7 in the localization of dsh, a PTK7 deletion construct deficient in dsh binding inhibits neural crest migration. Furthermore, the PTK7-mediated membrane localization of a dsh deletion mutant lacking PCP activity inhibits neural crest migration. Thus, PTK7 regulates neural crest migration by recruiting dsh, providing molecular evidence of how PTK7 intersects with the PCP signaling pathway to regulate vertebrate cell movements.
authors.affiliation: Department of Developmental Biochemistry, Center for Molecular Physiology of the Brain (CMPB 37077 Goettingen, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Shnitsar
authors.forename: Annette
authors.initials: A
authors.lastname: Borchers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002465:Cell Movement; D016764:Cell Polarity; D017931:DNA Primers / Q000235:genetics; D000072261:Dishevelled Proteins; D008959:Models, Neurological; D046912:Multiprotein Complexes; D009432:Neural Crest / Q000166:cytology / Q000196:embryology*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology; D014981:Xenopus / Q000196:embryology* / Q000235:genetics / Q000502:physiology*; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; C492040:Fzd7 protein, Xenopus; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D029867:Xenopus Proteins; C487768:PTK7 protein, Xenopus; D020794:Receptor Protein-Tyrosine Kinases