Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2

Nat Genet. 2007 Oct;39(10):1225-34. doi: 10.1038/ng2112. Epub 2007 Sep 2.

Abstract

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 thatWnt11 signaling affects extracellular matrix composition, cytoskeletal rearrangements and polarized cell movement required for morphogenesis of the cardiac outflow tract. Notably, transforming growth factor beta2 (TGFbeta2), 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 --> TGFbeta2 pathway is critical in regulating morphogenesis in response to noncanonical Wnt signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factors / metabolism*
  • Animals
  • Base Sequence
  • Blood Proteins / metabolism*
  • Cell Lineage
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Down-Regulation
  • Heart / embryology
  • Heart / growth & development
  • Homeobox Protein PITX2
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • Morphogenesis / physiology*
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Transcriptional Activation*
  • Transforming Growth Factor beta2 / genetics*
  • Transforming Growth Factor beta2 / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism

Substances

  • Activating Transcription Factors
  • Blood Proteins
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Homeodomain Proteins
  • Tgfb2 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta2
  • Wnt Proteins
  • Wnt11 protein, mouse
  • beta Catenin

Associated data

  • GENBANK/AA511462
  • GENBANK/BF135240
  • GENBANK/BQ713524
  • GENBANK/BQ944558