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Molecular and Cellular Biology, June 2005, p. 5073-5083, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5073-5083.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum

Anne Pizard,^1,2 Patrick G. Burgon,^1,2 David L. Paul,³ Benoit G. Bruneau,^4,5 Christine E. Seidman,^1,2 and J. G. Seidman^1*

Department of Genetics, Harvard Medical School, and Howard Hughes Medical Institute,¹ Cardiovascular Division, Brigham and Women's Hospital,² Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115,³ Programs in Cardiovascular Research and Developmental Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8,⁴ Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8⁵

Received 3 November 2004/ Returned for modification 9 December 2004/ Accepted 14 March 2005

Haploinsufficiency of T-box transcription factor 5 (TBX5) causes human Holt-Oram syndrome (HOS), a developmental disorder characterized by skeletal and heart malformations. Mice carrying a Tbx5 null allele (Tbx5^+/) have malformations in digits, wrists, and sternum joints, regions where Tbx5 is expressed. We demonstrate that mice deficient in connexin 40 (Cx40), a Tbx5-regulated gap junction component, shared axial and appendicular skeletal malformations with Tbx5^+/ mice. Although no role in skeleton patterning has been described for gap junctions, we demonstrate here that Cx40 is involved in formation of specific joints, as well as bone shape. Even a 50% reduction in either Tbx5 or Cx40 produces bone abnormalities, demonstrating their crucial control over skeletal development. Further, we demonstrate that Tbx5 exerts in part its key regulatory role in bone growth and maturation by controlling via Cx40 the expression of Sox9 (a transcription factor essential for chondrogenesis and skeleton growth). Our study strongly suggests that Cx40 deficiency accounts for many skeletal malformations in HOS and that Tbx5 regulation of Cx40 plays a critical role in the exquisite developmental patterning of the forelimbs and sternum.

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* Corresponding author. Mailing address: Harvard Medical School, Genetics Department, N.R.B. Room 256, 77 Louis Pasteur Avenue, Boston, MA 02115. Phone: (617) 432-7830. Fax: (617) 432-7832. E-mail: seidman{at}genetics.med.harvard.edu.

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Molecular and Cellular Biology, June 2005, p. 5073-5083, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5073-5083.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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