A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development

Ivan P G Moskowitz; Jae B Kim; Meredith L Moore; Cordula M Wolf; Michael A Peterson; Jay Shendure; Marcelo A Nobrega; Yoshifumi Yokota; Charles Berul; Seigo Izumo; J G Seidman; Christine E Seidman

doi:10.1016/j.cell.2007.04.036

A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development

Cell. 2007 Jun 29;129(7):1365-76. doi: 10.1016/j.cell.2007.04.036.

Authors

Ivan P G Moskowitz¹, Jae B Kim, Meredith L Moore, Cordula M Wolf, Michael A Peterson, Jay Shendure, Marcelo A Nobrega, Yoshifumi Yokota, Charles Berul, Seigo Izumo, J G Seidman, Christine E Seidman

Affiliation

¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

PMID: 17604724
DOI: 10.1016/j.cell.2007.04.036

Abstract

The cardiac conduction system is an anatomically discrete segment of specialized myocardium that initiates and propagates electrical impulses to coordinate myocardial contraction. To define the molecular composition of the mouse ventricular conduction system we used microdissection and transcriptional profiling by serial analysis of gene expression (SAGE). Conduction-system-specific expression for Id2, a member of the Id gene family of transcriptional repressors, was identified. Analyses of Id2-deficient mice demonstrated structural and functional conduction system abnormalities, including left bundle branch block. A 1.2 kb fragment of the Id2 promoter proved sufficient for cooperative regulation by Nkx2-5 and Tbx5 in vitro and for conduction-system-specific gene expression in vivo. Furthermore, compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system. We conclude that a molecular pathway including Tbx5, Nkx2-5, and Id2 coordinates specification of ventricular myocytes into the ventricular conduction system lineage.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Cell Line
Cell Lineage / physiology
Chlorocebus aethiops
Gene Expression Profiling
Gene Expression Regulation, Developmental / genetics*
Heart Conduction System / abnormalities*
Heart Conduction System / metabolism
Heart Defects, Congenital / genetics*
Heart Defects, Congenital / metabolism
Heart Ventricles / abnormalities*
Heart Ventricles / metabolism
Homeobox Protein Nkx-2.5
Homeodomain Proteins / genetics*
Inhibitor of Differentiation Protein 2 / deficiency
Inhibitor of Differentiation Protein 2 / genetics*
Mice
Mice, Knockout
Myocytes, Cardiac / metabolism
Promoter Regions, Genetic / genetics
Regulatory Elements, Transcriptional / genetics
Signal Transduction / genetics
T-Box Domain Proteins / deficiency
T-Box Domain Proteins / genetics*
Transcription Factors / deficiency
Transcription Factors / genetics*

Substances

Homeobox Protein Nkx-2.5
Homeodomain Proteins
Idb2 protein, mouse
Inhibitor of Differentiation Protein 2
Nkx2-5 protein, mouse
T-Box Domain Proteins
T-box transcription factor 5
Transcription Factors