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

Abstract

Transcriptional readout downstream of canonical Wnt signaling is known to be mediated by β-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 β-catenin pathway in developing heart and that Wnt11 mutants show cardiac outflow tract defects. We provide genetic and biochemical evidence thatWnt11 signaling affects extracellular matrix composition, cytoskeletal rearrangements and polarized cell movement required for morphogenesis of the cardiac outflow tract. Notably, transforming growth factor β2 (TGFβ2), 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 → TGFβ2 pathway is critical in regulating morphogenesis in response to noncanonical Wnt signaling.

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Figure 1: Wnt11 is a downstream target of Pitx2 and β-catenin in muscle cell lineages and developing heart.
Figure 2: Abnormal outflow tract and great vessel development in Wnt11−/− mutants.
Figure 3: Tgfb2 as a target of the Pitx2 → Wnt11 signaling pathway.
Figure 4: Tgfb2 is regulated by a Wnt11 → JNK → ATF/CREB pathway.
Figure 5: Immunofluorescence analysis of sections from wild-type and Wnt11 and Tgfb2 mutant embryos.
Figure 6: Immunofluorescence analysis of endothelial cells from wild-type and Wnt11 mutant embryos.

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Acknowledgements

We thank A. Kispert (MH Hannover) for providing the Wnt11-transfected NIH3T3 cells, S. Ishii for providing the ATF2 mutant embryos and C. Marcelle for discussions and for sharing data before publication. We are grateful to J. Miner (Washington University) for providing us with the laminin α-5 antibody. We thank M. McCurdy, H. Taylor, L. Yang, L. Bu, X. Zhu, K.A. Ohgi, J. Zhao and C. Nelson for their technical assistance, J. Chen for helpful discussion and H. Taylor for animal husbandry. We also thank J. Hightower for figure preparation. M.G.R. is an investigator with the Howard Hughes Medical Institute. This work was supported by US National Institutes of Health (NIH) grants HL74066, HL66276 and HL70867 (to S.M.E.); NIH grants HL65445 and DK18477 (to M.G.R.); NIH grant DK054364 (to A.P.M.); American Heart Association grant 0525141Y (to L.L.) and a Research Career Award from the US National Institute of Diabetes and Digestive and Kidney Diseases grant DK 064744 (to X.L.).

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W.Z. and L.L. contributed equally to this work, and their names are interchangeable in this paper.

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Correspondence to Michael G Rosenfeld or Sylvia M Evans.

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Zhou, W., Lin, L., Majumdar, A. et al. Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family–mediated transcriptional activation of TGFβ2. Nat Genet 39, 1225–1234 (2007). https://doi.org/10.1038/ng2112

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