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

Nature Genetics volume 39, pages 12251234 (2007) | Download Citation

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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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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.).

Author information

Author notes

    • Wenlai Zhou
    •  & Lizhu Lin

    These authors contributed equally to this work.

Affiliations

  1. Howard Hughes Medical Institute and Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.

    • Wenlai Zhou
    • , Xue Li
    •  & Michael G Rosenfeld
  2. Skaggs School of Pharmacy, Departments of Pharmacology and Medicine, University of California, San Diego, La Jolla, California 92093, USA.

    • Lizhu Lin
    • , Xiaoxue Zhang
    • , Yunqing Shi
    •  & Sylvia M Evans
  3. Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg2, Plan 4 B1, SE-171 77 Stockholm, Sweden.

    • Arindam Majumdar
  4. Alkek Institute of Biosciences and Technology, Texas A&M System Health Science Center, Houston, Texas 77030, USA.

    • Wei Liu
    •  & James Martin
  5. Department of Pediatrics, the Comprehensive Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.

    • Leah Etheridge
    •  & Anthony Wynshaw-Boris
  6. Laboratory for Molecular Oncology, Department of Human Genetics, University of Leuven, B-3000, Belgium.

    • Wim Van de Ven
  7. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Vesa Kaartinen
  8. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Andrew P McMahon

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Contributions

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

Corresponding authors

Correspondence to Michael G Rosenfeld or Sylvia M Evans.

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DOI

https://doi.org/10.1038/ng2112

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