Avian Facial Morphogenesis Is Regulated by c-Jun N-terminal Kinase/Planar Cell Polarity (JNK/PCP) Wingless-related (WNT) Signaling

作者：Geetha Loganathan Poongodi; Nimmagadda Suresh; Fu Katherine; Richman Joy M^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(35): 24153-24167.

DOI：10.1074/jbc.M113.522003

• Cell Migration
• Craniofacial Development
• Embryo
• Morphogenesis
• Retrovirus
• Cleft Lip
• Disheveled
• Luciferase Reporter Assay
• Micromass Culture
• Optical Projection Tomography

Background: Numerous genes contribute to the increased risk of facial clefting, but the cellular mechanisms involved are not well understood. Results: JNK/PCP wingless-related signaling is demonstrated as a major regulator of face shape. Conclusion: WNT11 induces clefting via inhibiting proliferation, compressing facial prominences, and changing cell behavior. Significance: JNK/PCP WNT signaling is implicated in the pathophysiology underlying craniofacial abnormalities.
Wingless-related proteins (WNTs) regulate extension of the central axis of the vertebrate embryo (convergent extension) as well as morphogenesis of organs such as limbs and kidneys. Here, we asked whether WNT signaling directs facial morphogenesis using a targeted approach in chicken embryos. WNT11 is thought to mainly act via -catenin-independent pathways, and little is 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 due in part to decreased proliferation. We next determined, using a series of luciferase reporters, that WNT11 strongly induced JNK/planar cell polarity signaling while repressing the -catenin-mediated pathway. The activation of the JNK-ATF2 reporter was mediated by the DEP domain of Dishevelled. The impacts of altered signaling on the mesenchyme were assessed by implanted Wnt11- or Wnt3a-expressing cells (activates -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/planar cell polarity WNT signaling operates in the face to regulate several morphogenetic events leading to lip fusion.

• 出版日期2014-8-29