Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation.
The planar cell polarity (PCP) pathway is conserved throughout evolution, but it mediates distinct developmental processes. In Drosophila, members of the PCP pathway localize in a polarized fashion to specify the cellular polarity within the plane of the epithelium, perpendicular to the apicobasal axis of the cell. In Xenopus and zebrafish, several homologs of the components of the fly PCP pathway control convergent extension. We have shown previously that mammalian PCP homologs regulate both cell polarity and polarized extension in the cochlea in the mouse. Here we show, using mice with null mutations in two mammalian Dishevelled homologs, Dvl1 and Dvl2, that during neurulation a homologous mammalian PCP pathway regulates concomitant lengthening and narrowing of the neural plate, a morphogenetic process defined as convergent extension. Dvl2 genetically interacts with Loop-tail, a point mutation in the mammalian PCP gene Vangl2, during neurulation. By generating Dvl2 BAC (bacterial artificial chromosome) transgenes and introducing different domain deletions and a point mutation identical to the dsh1 allele in fly, we further demonstrated a high degree of conservation between Dvl function in mammalian convergent extension and the PCP pathway in fly. In the neuroepithelium of neurulating embryos, Dvl2 shows DEP domain-dependent membrane localization, a pre-requisite for its involvement in convergent extension. Intriguing, the Loop-tail mutation that disrupts both convergent extension in the neuroepithelium and PCP in the cochlea does not disrupt Dvl2 membrane distribution in the neuroepithelium, in contrast to its drastic effect on Dvl2 localization in the cochlea. These results are discussed in light of recent models on PCP and convergent extension.
Department of Pediatrics and Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0627, La Jolla, CA 92093-0627, USA.
Jianbo
J
Wang
Natasha S
NS
Hamblet
Sharayne
S
Mark
Mary E
ME
Dickinson
Brendan C
BC
Brinkman
Neil
N
Segil
Scott E
SE
Fraser
Ping
P
Chen
John B
JB
Wallingford
Anthony
A
Wynshaw-Boris
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016764:Cell Polarity; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008818:Mice, Neurologic Mutants; D008957:Models, Genetic; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D019076:Transgenes; D029867:Xenopus Proteins
D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; D010750:Phosphoproteins; D029867:Xenopus Proteins; C000606588:dsh protein, Drosophila