Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFβ2

Transcriptional readout downstream of canonical Wnt signaling is known to be mediated by beta-catenin activation of well-described targets, but potential transcriptional readout in response to noncanonical Wnt signaling remains poorly understood. Here, we define a transcriptional pathway important in noncanonical Wnt signaling. We have found that Wnt11 is a direct target of a canonical beta-catenin pathway in developing heart and that Wnt11 mutants show cardiac outflow tract defects. We provide genetic and biochemical evidence that Wnt11 signaling affects extracellular matrix composition, cytoskeletal rearrangements and polarized cell movement required for morphogenesis of the cardiac outflow tract. Notably, transforming growth factor beta 2 (TGF beta 2), a key effector of organ morphogenesis, is regulated by Wnt11- mediated noncanonical signaling in developing heart and somites via one or more activating transcription factor (ATF)/cyclic AMP response element binding protein ( CREB) family members. Thus, we propose that transcriptional readout mediated at least in part by a Wnt11 -> ATF/CREB -> TGF beta 2 pathway is critical in regulating morphogenesis in response to noncanonical Wnt signaling.