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First published online 17 December 2008
doi: 10.1242/dev.030007

Development 136, 495-505 (2009)
Published by The Company of Biologists 2009
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Prox1 maintains muscle structure and growth in the developing heart

Catherine A. Risebro1, Richelle G. Searles1, Athalie A. D. Melville1, Elisabeth Ehler2, Nipurna Jina3, Sonia Shah4, Jacky Pallas4, Mike Hubank3, Miriam Dillard5, Natasha L. Harvey6, Robert J. Schwartz7, Kenneth R. Chien8,9, Guillermo Oliver5 and Paul R. Riley1,*

1 Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
2 The Randall Centre of Cell and Molecular Biophysics and The Cardiovascular Division, King's College, London SE1 1UL, UK.
3 Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
4 Bloomsbury Centre for Bioinformatics, Department of Computer Science, University College London, Gower Street, London WC1E 6BT, UK.
5 Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
6 Division of Haematology, The Hanson Institute, Adelaide, South Australia 5000, Australia.
7 Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
8 Massachusetts General Hospital Cardiovascular Research Center, Boston, MA 02114, USA.
9 Department of Cell Biology, Harvard Medical School, and the Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

* Author for correspondence (e-mail: p.riley{at}ich.ucl.ac.uk)

Accepted 21 November 2008

Impaired cardiac muscle growth and aberrant myocyte arrangement underlie congenital heart disease and cardiomyopathy. We show that cardiac-specific inactivation of the murine homeobox transcription factor Prox1 results in the disruption of expression and localisation of sarcomeric proteins, gross myofibril disarray and growth-retarded hearts. Furthermore, we demonstrate that Prox1 is required for direct transcriptional regulation of the genes encoding the structural proteins {alpha}-actinin, N-RAP and zyxin, which collectively function to maintain an actin-{alpha}-actinin interaction as the fundamental association of the sarcomere. Aspects of abnormal heart development and the manifestation of a subset of muscular-based disease have previously been attributed to mutations in key structural proteins. Our study reveals an essential requirement for direct transcriptional regulation of sarcomere integrity, in the context of enabling foetal cardiomyocyte hypertrophy, maintenance of contractile function and progression towards inherited or acquired myopathic disease.

Key words: Prox1, Mouse, Heart development, Myocardium, Sarcomere, Hypertrophy, Myopathy, N-RAP (Nrap), Zyxin


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