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First published online August 2, 2004
doi: 10.1242/10.1242/dev.01265

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The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system

¹ Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA
² Department of Pathology and Cardiac Registry, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
³ Molecular Cardiology Research Center and Section of Cardiac Electrophysiology, University of Pennsylvania, Philadelphia, PA 19104, USA
⁴ Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
⁵ Programs in Cardiovascular Research and Developmental Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
⁶ Department of Molecular and Medical Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
⁷ Departments of Anesthesiology and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA
⁸ Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA
⁹ Division of Cardiology, Brigham and Women's Hospital, and Howard Hughes Medical Institute, Boston, MA 02115,USA

^* Author for correspondence (e-mail: seidman{at}genetics.med.Harvard.edu)

Accepted 4 May 2004

We report a critical role for the T-box transcription factor Tbx5 in development and maturation of the cardiac conduction system. We find that Tbx5 is expressed throughout the central conduction system, including the atrioventricular bundle and bundle branch conduction system. Tbx5 haploinsufficiency in mice (Tbx5^del/+), a model of human Holt–Oram syndrome, caused distinct morphological and functional defects in the atrioventricular and bundle branch conduction systems. In the atrioventricular canal, Tbx5 haploinsufficiency caused a maturation failure of conduction system morphology and function. Electrophysiologic testing of Tbx5^del/+ mice suggested a specific atrioventricular node maturation failure. In the ventricular conduction system, Tbx5 haploinsufficiency caused patterning defects of both the left and right ventricular bundle branches, including absence or severe abnormalities of the right bundle branch. Absence of the right bundle branch correlated with right-bundle-branch block by ECG. Deficiencies in the gap junction protein gene connexin 40 (Cx40), a downstream target of Tbx5, did not account for morphologic conduction system defects in Tbx5^del/+ mice. We conclude that Tbx5 is required for Cx40-independent patterning of the cardiac conduction system, and suggest that the electrophysiologic defects in Holt–Oram syndrome reflect a developmental abnormality of the conduction system.

Key words: Cardiac, Conduction, Tbx5, Mouse

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