Wnt-5A/Ror2 Regulate Expression of XPAPC through an Alternative Noncanonical Signaling Pathway

Abstract

XWnt-5A, a member of the nontransforming Wnt-5A class of Wnt ligands, is required for convergent extension movements in Xenopus embryos. XWnt-5A knockdown phenocopies paraxial protocadherin (XPAPC) loss of function: involuted mesodermal cells fail to align mediolaterally, which results in aberrant movements and a selective inhibition of constriction. XWnt-5A depletion was rescued by coinjection of XPAPC RNA, indicating that XWnt-5A acts upstream of XPAPC. XWnt-5A, but not XWnt-11, stimulates XPAPC expression independent of the canonical Wnt/beta-catenin pathway. We show that transcriptional regulation of XPAPC by XWnt-5A requires the receptor tyrosine kinase Ror2. XWnt-5A/Xror2 signal through PI3 kinase and cdc42 to activate the JNK signaling cascade with the transcription factors ATF2 and c-jun. The Wnt-5A/Ror2 pathway represents an alternative, distinct branch of noncanonical Wnt signaling that controls gene expression and is required in the regulation of convergent extension movements in Xenopus gastrulation.