A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development.
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.
Moskowitz
Ivan P G
IP
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Kim
Jae B
JB
Moore
Meredith L
ML
Wolf
Cordula M
CM
Peterson
Michael A
MA
Shendure
Jay
J
Nobrega
Marcelo A
MA
Yokota
Yoshifumi
Y
Berul
Charles
C
Izumo
Seigo
S
Seidman
J G
JG
Seidman
Christine E
CE
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology; D002522:Chlorocebus aethiops; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006329:Heart Conduction System / Q000002:abnormalities* / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D006352:Heart Ventricles / Q000002:abnormalities* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D051797:Inhibitor of Differentiation Protein 2 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; C484469:Nkx2-5 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors