MEKK3 initiates transforming growth factor β2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis

Mark V. Stevens, Derrick M. Broka, Patti Parker, Elisa Rogowitz, Richard Vaillancourt, Todd D Camenisch

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3 attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFβ2, Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFβ2-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.

Original languageEnglish (US)
Pages (from-to)1430-1440
Number of pages11
JournalCirculation Research
Volume103
Issue number12
DOIs
StatePublished - Dec 5 2008

Fingerprint

Endocardial Cushions
Epithelial-Mesenchymal Transition
Transforming Growth Factors
Morphogenesis
Mesoderm
Congenital Heart Defects
Endocardium
Mitogen-Activated Protein Kinase 3
Embryonic Development
Phosphotransferases

Keywords

  • Endocardial cushions
  • Epithelial-to-mesenchymal transition
  • Heart
  • MEKK3
  • TGFΒ2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

MEKK3 initiates transforming growth factor β2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis. / Stevens, Mark V.; Broka, Derrick M.; Parker, Patti; Rogowitz, Elisa; Vaillancourt, Richard; Camenisch, Todd D.

In: Circulation Research, Vol. 103, No. 12, 05.12.2008, p. 1430-1440.

Research output: Contribution to journalArticle

@article{9bd9fafc0e53466580a4c9a36f2a77b2,
title = "MEKK3 initiates transforming growth factor β2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis",
abstract = "Congenital heart defects occur at a rate of 5{\%} and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3 attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFβ2, Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFβ2-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.",
keywords = "Endocardial cushions, Epithelial-to-mesenchymal transition, Heart, MEKK3, TGFΒ2",
author = "Stevens, {Mark V.} and Broka, {Derrick M.} and Patti Parker and Elisa Rogowitz and Richard Vaillancourt and Camenisch, {Todd D}",
year = "2008",
month = "12",
day = "5",
doi = "10.1161/CIRCRESAHA.108.180752",
language = "English (US)",
volume = "103",
pages = "1430--1440",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

TY - JOUR

T1 - MEKK3 initiates transforming growth factor β2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis

AU - Stevens, Mark V.

AU - Broka, Derrick M.

AU - Parker, Patti

AU - Rogowitz, Elisa

AU - Vaillancourt, Richard

AU - Camenisch, Todd D

PY - 2008/12/5

Y1 - 2008/12/5

N2 - Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3 attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFβ2, Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFβ2-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.

AB - Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3 attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFβ2, Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFβ2-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.

KW - Endocardial cushions

KW - Epithelial-to-mesenchymal transition

KW - Heart

KW - MEKK3

KW - TGFΒ2

UR - http://www.scopus.com/inward/record.url?scp=58149394173&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149394173&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.108.180752

DO - 10.1161/CIRCRESAHA.108.180752

M3 - Article

C2 - 19008476

AN - SCOPUS:58149394173

VL - 103

SP - 1430

EP - 1440

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 12

ER -