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, A. Czirók, Todd D. Camenisch, Joey V. Barnett

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

Fingerprint

Proteins
Fibroblast Growth Factor 2
Coronary Vessels
Embryonic Structures
Cell Proliferation
Growth Factor Receptors
Pericardium
Transforming Growth Factors
Intercellular Signaling Peptides and Proteins
Amino Acids
Genes
In Vitro Techniques

Keywords

  • Coronary vessels
  • Epicardium
  • TGFβ
  • TGFβR3

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

Cite this

Sánchez, N. S., Hill, C. R., Love, J. D., Soslow, J. H., Craig, E., Austin, A. F., ... 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

The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. / Sánchez, Nora S.; Hill, Cynthia R.; Love, Joseph D.; Soslow, Jonathan H.; Craig, Evisabel; Austin, Anita F.; Brown, Christopher B.; Czirók, A.; Camenisch, Todd D.; Barnett, Joey V.

In: Developmental Biology, Vol. 358, No. 2, 15.10.2011, p. 331-343.

Research output: Contribution to journalArticle

Sánchez, NS, Hill, CR, Love, JD, Soslow, JH, Craig, E, Austin, AF, Brown, CB, Czirók, A, Camenisch, TD & Barnett, JV 2011, 'The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior', Developmental Biology, vol. 358, no. 2, pp. 331-343. https://doi.org/10.1016/j.ydbio.2011.08.008
Sánchez, Nora S. ; Hill, Cynthia R. ; Love, Joseph D. ; Soslow, Jonathan H. ; Craig, Evisabel ; Austin, Anita F. ; Brown, Christopher B. ; Czirók, A. ; Camenisch, Todd D. ; Barnett, Joey V. / The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. In: Developmental Biology. 2011 ; Vol. 358, No. 2. pp. 331-343.
@article{17cb23bd12af4614867b3c720cf2a67f,
title = "The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior",
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.",
keywords = "Coronary vessels, Epicardium, TGFβ, TGFβR3",
author = "S{\'a}nchez, {Nora S.} and Hill, {Cynthia R.} and Love, {Joseph D.} and Soslow, {Jonathan H.} and Evisabel Craig and Austin, {Anita F.} and Brown, {Christopher B.} and A. Czir{\'o}k and Camenisch, {Todd D.} and Barnett, {Joey V.}",
year = "2011",
month = "10",
day = "15",
doi = "10.1016/j.ydbio.2011.08.008",
language = "English",
volume = "358",
pages = "331--343",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior

AU - Sánchez, Nora S.

AU - Hill, Cynthia R.

AU - Love, Joseph D.

AU - Soslow, Jonathan H.

AU - Craig, Evisabel

AU - Austin, Anita F.

AU - Brown, Christopher B.

AU - Czirók, A.

AU - Camenisch, Todd D.

AU - Barnett, Joey V.

PY - 2011/10/15

Y1 - 2011/10/15

N2 - 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.

AB - 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.

KW - Coronary vessels

KW - Epicardium

KW - TGFβ

KW - TGFβR3

UR - http://www.scopus.com/inward/record.url?scp=80053096165&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053096165&partnerID=8YFLogxK

U2 - 10.1016/j.ydbio.2011.08.008

DO - 10.1016/j.ydbio.2011.08.008

M3 - Article

C2 - 21871877

AN - SCOPUS:80053096165

VL - 358

SP - 331

EP - 343

JO - Developmental Biology

JF - Developmental Biology

SN - 0012-1606

IS - 2

ER -