BMP10 is essential for maintaining cardiac growth during murine cardiogenesis

Hanying Chen, Shu Shi, Lourdes Acosta, Weiming Li, Jonathan Lu, Shideng Bao, Zhuang Chen, Zuocheng Yang, Michael D. Schneider, Kenneth R. Chien, Simon Conway, Mervin Yoder, Laura Haneline, Diego Franco, Weinian Shou

Research output: Contribution to journalArticle

282 Citations (Scopus)

Abstract

During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition,. which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57kip2 and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.

Original languageEnglish
Pages (from-to)2219-2231
Number of pages13
JournalDevelopment (Cambridge)
Volume131
Issue number9
DOIs
StatePublished - May 2004

Fingerprint

Bone Morphogenetic Proteins
Growth
Embryonic Structures
Pregnancy
Myocardium
Tacrolimus Binding Proteins
Cell Cycle Proteins
Congenital Heart Defects
Ventricular Heart Septal Defects
Conditioned Culture Medium
Cardiac Myocytes
Heart Diseases
Transcription Factors
Hemodynamics
Cytokines

Keywords

  • BMP10
  • Cardiac growth
  • Compaction
  • MEF2C
  • NKX2.5
  • p57
  • Ventricular trabeculation

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. / Chen, Hanying; Shi, Shu; Acosta, Lourdes; Li, Weiming; Lu, Jonathan; Bao, Shideng; Chen, Zhuang; Yang, Zuocheng; Schneider, Michael D.; Chien, Kenneth R.; Conway, Simon; Yoder, Mervin; Haneline, Laura; Franco, Diego; Shou, Weinian.

In: Development (Cambridge), Vol. 131, No. 9, 05.2004, p. 2219-2231.

Research output: Contribution to journalArticle

Chen, H, Shi, S, Acosta, L, Li, W, Lu, J, Bao, S, Chen, Z, Yang, Z, Schneider, MD, Chien, KR, Conway, S, Yoder, M, Haneline, L, Franco, D & Shou, W 2004, 'BMP10 is essential for maintaining cardiac growth during murine cardiogenesis', Development (Cambridge), vol. 131, no. 9, pp. 2219-2231. https://doi.org/10.1242/dev.01094
Chen, Hanying ; Shi, Shu ; Acosta, Lourdes ; Li, Weiming ; Lu, Jonathan ; Bao, Shideng ; Chen, Zhuang ; Yang, Zuocheng ; Schneider, Michael D. ; Chien, Kenneth R. ; Conway, Simon ; Yoder, Mervin ; Haneline, Laura ; Franco, Diego ; Shou, Weinian. / BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. In: Development (Cambridge). 2004 ; Vol. 131, No. 9. pp. 2219-2231.
@article{91180da93baa4d098393d8d0089002aa,
title = "BMP10 is essential for maintaining cardiac growth during murine cardiogenesis",
abstract = "During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition,. which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57kip2 and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.",
keywords = "BMP10, Cardiac growth, Compaction, MEF2C, NKX2.5, p57, Ventricular trabeculation",
author = "Hanying Chen and Shu Shi and Lourdes Acosta and Weiming Li and Jonathan Lu and Shideng Bao and Zhuang Chen and Zuocheng Yang and Schneider, {Michael D.} and Chien, {Kenneth R.} and Simon Conway and Mervin Yoder and Laura Haneline and Diego Franco and Weinian Shou",
year = "2004",
month = "5",
doi = "10.1242/dev.01094",
language = "English",
volume = "131",
pages = "2219--2231",
journal = "Development",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "9",

}

TY - JOUR

T1 - BMP10 is essential for maintaining cardiac growth during murine cardiogenesis

AU - Chen, Hanying

AU - Shi, Shu

AU - Acosta, Lourdes

AU - Li, Weiming

AU - Lu, Jonathan

AU - Bao, Shideng

AU - Chen, Zhuang

AU - Yang, Zuocheng

AU - Schneider, Michael D.

AU - Chien, Kenneth R.

AU - Conway, Simon

AU - Yoder, Mervin

AU - Haneline, Laura

AU - Franco, Diego

AU - Shou, Weinian

PY - 2004/5

Y1 - 2004/5

N2 - During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition,. which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57kip2 and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.

AB - During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition,. which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57kip2 and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.

KW - BMP10

KW - Cardiac growth

KW - Compaction

KW - MEF2C

KW - NKX2.5

KW - p57

KW - Ventricular trabeculation

UR - http://www.scopus.com/inward/record.url?scp=2042462926&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2042462926&partnerID=8YFLogxK

U2 - 10.1242/dev.01094

DO - 10.1242/dev.01094

M3 - Article

C2 - 15073151

AN - SCOPUS:2042462926

VL - 131

SP - 2219

EP - 2231

JO - Development

JF - Development

SN - 0950-1991

IS - 9

ER -