ACS DIVISION OF BIOLOGICAL CHEMISTRY

July 9th, 2014 by Geetha-Loganathan, P., Nimmagadda, S., Fu, K., Richman, J. M.

Wingless-related proteins (WNTs) regulate extension of the central axis of the vertebrate embryo (convergent extension, CE) as well as morphogenesis of organs such as limbs and kidneys. Here we ask whether WNT signaling directs facial morphogenesis using a targeted approach in chicken embryos. WNT11 is thought to be mainly act via β catenin-independent pathways and little was known about its role in craniofacial development. RCAS::WNT11 retrovirus was injected into the maxillary prominence and the majority of embryos developed notches in the upper beak or the equivalent of cleft lip. Three-dimensional morphometric analysis revealed that WNT11 prevented lengthening of the maxillary prominence which was in part due to decreased proliferation. We next determined using a series of luciferase reporters that WNT11 strongly induced JNK/PCP signaling while repressing the β catenin-mediated pathway. The activation of the JNK-ATF2 reporter was mediated by the DEP domain of Dishevelled. The impacts of altered signaling on mesenchyme were assessed by implanted Wnt11 or Wnt3a expressing cells (activates β catenin pathway) into the maxillary prominence or by knocking down endogenous WNT11 with RNAi. Host cells were attracted to Wnt11 donor cells. In contrast, cells exposed to Wnt3a or the control cells did not migrate. Cells in which endogenous WNT11 was knocked down were more oriented and shorter than those exposed to exogenous WNT11. The data suggest that JNK/PCP WNT signaling operates in the face to regulate several morphogenetic events leading to lip fusion.