Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality

Olga Simmons, Paige Snider, Jain Wang, Robert J. Schwartz, Yiping Chen, Simon Conway

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late-differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over-expression of extracellular BMP antagonist Noggin. Results: Using Nkx2.5-Cre to drive lineage-restricted Noggin within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1/5/8 expression. Noggin mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin-myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin-expressing regions in the early heart's pacemaker region, failed to express the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4), resulting in an overall decrease in Hcn4 levels. Conclusions: Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker.

Original languageEnglish
Pages (from-to)457-467
Number of pages11
JournalDevelopmental Dynamics
Volume244
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Morphogenesis
Cardiac Myocytes
Bone Morphogenetic Proteins
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Myosins
Heart Arrest
Actin Cytoskeleton
Potassium
Cell Death
Sodium
Cell Proliferation
Electrons
Genes

Keywords

  • BMP
  • Bradycardia
  • Cardiomyocyte
  • Congenital heart defects
  • Contractile apparatus
  • Mouse embryo
  • Noggin
  • Proliferation
  • Transgenic overexpression

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality. / Simmons, Olga; Snider, Paige; Wang, Jain; Schwartz, Robert J.; Chen, Yiping; Conway, Simon.

In: Developmental Dynamics, Vol. 244, No. 3, 01.03.2015, p. 457-467.

Research output: Contribution to journalArticle

Simmons, Olga ; Snider, Paige ; Wang, Jain ; Schwartz, Robert J. ; Chen, Yiping ; Conway, Simon. / Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality. In: Developmental Dynamics. 2015 ; Vol. 244, No. 3. pp. 457-467.
@article{d94b63c3abd84a608d93a6eeb6487393,
title = "Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality",
abstract = "Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late-differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over-expression of extracellular BMP antagonist Noggin. Results: Using Nkx2.5-Cre to drive lineage-restricted Noggin within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1/5/8 expression. Noggin mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin-myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin-expressing regions in the early heart's pacemaker region, failed to express the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4), resulting in an overall decrease in Hcn4 levels. Conclusions: Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker.",
keywords = "BMP, Bradycardia, Cardiomyocyte, Congenital heart defects, Contractile apparatus, Mouse embryo, Noggin, Proliferation, Transgenic overexpression",
author = "Olga Simmons and Paige Snider and Jain Wang and Schwartz, {Robert J.} and Yiping Chen and Simon Conway",
year = "2015",
month = "3",
day = "1",
doi = "10.1002/dvdy.24233",
language = "English",
volume = "244",
pages = "457--467",
journal = "Developmental Dynamics",
issn = "1058-8388",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality

AU - Simmons, Olga

AU - Snider, Paige

AU - Wang, Jain

AU - Schwartz, Robert J.

AU - Chen, Yiping

AU - Conway, Simon

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late-differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over-expression of extracellular BMP antagonist Noggin. Results: Using Nkx2.5-Cre to drive lineage-restricted Noggin within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1/5/8 expression. Noggin mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin-myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin-expressing regions in the early heart's pacemaker region, failed to express the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4), resulting in an overall decrease in Hcn4 levels. Conclusions: Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker.

AB - Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late-differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over-expression of extracellular BMP antagonist Noggin. Results: Using Nkx2.5-Cre to drive lineage-restricted Noggin within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1/5/8 expression. Noggin mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin-myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin-expressing regions in the early heart's pacemaker region, failed to express the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4), resulting in an overall decrease in Hcn4 levels. Conclusions: Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker.

KW - BMP

KW - Bradycardia

KW - Cardiomyocyte

KW - Congenital heart defects

KW - Contractile apparatus

KW - Mouse embryo

KW - Noggin

KW - Proliferation

KW - Transgenic overexpression

UR - http://www.scopus.com/inward/record.url?scp=84924023801&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924023801&partnerID=8YFLogxK

U2 - 10.1002/dvdy.24233

DO - 10.1002/dvdy.24233

M3 - Article

C2 - 25428115

AN - SCOPUS:84924023801

VL - 244

SP - 457

EP - 467

JO - Developmental Dynamics

JF - Developmental Dynamics

SN - 1058-8388

IS - 3

ER -