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Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development.

ABSTRACT: The ventricular myocardium is the most prominent layer of the heart, and the most important for mediating cardiac physiology. Although the ventricular myocardium is critical for heart function, the cellular hierarchy responsible for ventricle-specific myocardium development remains unresolved.To determine the pattern and time course of ventricular myocardium development, we investigated IRX4 protein expression, which has not been previously reported. We identified IRX4+ cells in the cardiac crescent, and these cells were positive for markers of the first or second heart fields. From the onset of chamber formation, IRX4+ cells were restricted to the ventricular myocardium. This expression pattern persisted into adulthood. Of interest, we observed that IRX4 exhibits developmentally regulated dynamic intracellular localization. Throughout prenatal cardiogenesis, and up to postnatal day 4, IRX4 was detected in the cytoplasm of ventricular myocytes. However, between postnatal days 5–6, IRX4 translocated to the nucleus of ventricular myocytes.Given the ventricle-specific expression of Irx4 in later stages of heart development, we hypothesize that IRX4+ cells in the cardiac crescent represent the earliest cell population in the cellular hierarchy underlying ventricular myocardium development.

SUBMITTER: Nelson DO

PROVIDER: S-EPMC4005848 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development.

Nelson Daryl O DO Jin Dexter X DX Downs Karen M KM Kamp Timothy J TJ Lyons Gary E GE

Developmental dynamics : an official publication of the American Association of Anatomists 20140301 3

<h4>Background</h4>The ventricular myocardium is the most prominent layer of the heart, and the most important for mediating cardiac physiology. Although the ventricular myocardium is critical for heart function, the cellular hierarchy responsible for ventricle-specific myocardium development remains unresolved.<h4>Results</h4>To determine the pattern and time course of ventricular myocardium development, we investigated IRX4 protein expression, which has not been previously reported. We identif ...[more]

PMID: 24123507

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Project description:Ventricular chambers are essential for the rhythmic contraction and relaxation that occurs in every hearbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is still poorly understood. Here we show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation and later coordinates ventricular patterning and compaction with coronary vessel development to give rise to the mature chamber via a temporal sequence of ligand signalling determined by the glycosyltransferase Manic Fringe (Mfng). The early endocardial expression of Mfng favours Dll4-Notch1 signalling, Which induces trabeculation in the developing ventricle.Ventricular maturation and compaction in turn require Mfng and Dll4 downregulation in the endocardium, Which allows myocardial Jag1- And Jag2- Signalling to Notch1 in this tissue.Timely and spatial perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies. Dll4 and Notch1 conditional KOs using Nfact1 and/or Tie2 driven Cre expression: RNA was isolated from pooled whole hearts of 8 (Nfact1) or 9 (Tie2) E9.5 embryos per replicate. Dll4flox;Nfatc1-Cre and WT siblings (4 KO and 4 WT replicates), Notch1flox;Nfatc1-Cre and WT siblings (3 KO and 2 WT replicates), Dll4flox;Tie2-Cre and WT siblings (3 KO and 3 WT replicates). Jag1, Jag2 and Jag1Jag2 conditional KOs using cTnT driven Cre expression: RNA was isolated from pooled heart ventricles of 4 E15.5 embryos per replicate. Jag1flox;cTnT-Cre and WT siblings (3 KO and 3 WT replicates), Jag2flox;cTnT-Cre and WT siblings (3 KO and 2 WT replicates). Jag1flox;jag2flox;cTnT-Cre and WT siblings (3 KO and 2 WT replicates). MFng Gain Of Function using Tie2 driven Cre expression: RNA was isolated from pooled heart ventricles of 4 E15.5 embryos per replicate. MFng;Tie2-Cre and WT siblings (4 GOF and 4 WT replicates). For Dll4, Noth1 and Jag1 KOs, libraries were prepared using the standard Illumina TrueSeq RNASeq library preparation kit and sequenced in a GAIIx Illumina sequencer using a 75bp single end elongation protocol. For Jag2 and Jag1Jag2 KOs and MFng GOF libraries were prepared prepared using the NEBNext Ultra RNA Library Prep Kit for Illumina and sequenced in a HiSeq2500 Illumina sequencer using a 61bp single end elongation protocol

Dataset Information

Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development.

Publications

Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development.

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