The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior

Nora S. Sánchez, Cynthia R. Hill, Joseph D. Love, Jonathan H. Soslow, Evisabel Craig, Anita F. Austin, Christopher B. Brown, Andras Czirok, Todd D. Camenisch, Joey V. Barnett

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Abstract

The epicardium is a major contributor of the cells that are required for the formation of coronary vessels. Mice lacking both copies of the gene encoding the Type III Transforming Growth Factor β Receptor (TGFβR3) fail to form the coronary vasculature, but the molecular mechanism by which TGFβR3 signals coronary vessel formation is unknown. We used intact embryos and epicardial cells from E11.5 mouse embryos to reveal the mechanisms by which TGFβR3 signals and regulates epicardial cell behavior. Analysis of E13.5 embryos reveals a lower rate of epicardial cell proliferation and decreased epicardially derived cell invasion in Tgfbr3-/- hearts. Tgfbr3-/- epicardial cells in vitro show decreased proliferation and decreased invasion in response to TGFβ1 and TGFβ2. Unexpectedly, loss of TGFβR3 also decreases responsiveness to two other important regulators of epicardial cell behavior, FGF2 and HMW-HA. Restoring full length TGFβR3 in Tgfbr3-/- cells rescued deficits in invasion in vitro in response TGFβ1 and TGFβ2 as well as FGF2 and HMW-HA. Expression of TGFβR3 missing the 3 C-terminal amino acids that are required to interact with the scaffolding protein GIPC1 did not rescue any of the deficits. Overexpression of GIPC1 alone in Tgfbr3-/- cells did not rescue invasion whereas knockdown of GIPC1 in Tgfbr3+/+ cells decreased invasion in response to TGFβ2, FGF2, and HMW-HA. We conclude that TGFβR3 interaction with GIPC1 is critical for regulating invasion and growth factor responsiveness in epicardial cells and that dysregulation of epicardial cell proliferation and invasion contributes to failed coronary vessel development in Tgfbr3-/- mice.

Original languageEnglish
Pages (from-to)331-343
Number of pages13
JournalDevelopmental Biology
Volume358
Issue number2
DOIs
Publication statusPublished - Oct 15 2011

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Keywords

  • Coronary vessels
  • Epicardium
  • TGFβ
  • TGFβR3

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Sánchez, N. S., Hill, C. R., Love, J. D., Soslow, J. H., Craig, E., Austin, A. F., Brown, C. B., Czirok, A., Camenisch, T. D., & Barnett, J. V. (2011). The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. Developmental Biology, 358(2), 331-343. https://doi.org/10.1016/j.ydbio.2011.08.008