This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/7/813    most recent CIRCRESAHA.107.163188v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tessari, A. Articles by Campione, M. Search for Related Content PubMed PubMed Citation Articles by Tessari, A. Articles by Campione, M. Related Collections Structure Gene expression Genetics of cardiovascular disease Related Article

(Circulation Research. 2008;102:813.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Myocardial Pitx2 Differentially Regulates the Left Atrial Identity and Ventricular Asymmetric Remodeling Programs

Alessandra Tessari^*, Mara Pietrobon^*, Antonella Notte, Giuseppe Cifelli, Philip J. Gage, Michael D. Schneider, Giuseppe Lembo, Marina Campione

From the CNR Institute of Neurosciences (A.T., M.P., M.C.), Department of Biomedical Sciences, University of Padova, Italy; the Department of Angio-Cardio-Neurology (A.N., G.C., G.L.), IRCCS Neuromed, Polo Molise "Sapienza" University of Rome, Pozzilli (Isernia), Italy; Ophthalmology & Visual Sciences (P.J.G.), Cell & Developmental Biology, University of Michigan Medical School; and the Department of Cardiovascular Sciences (M.D.S.), National Heart and Lung Institute, Imperial College, London.

Correspondence to Marina Campione, CNR Institute of Neurosciences, Department of Biomedical Sciences, University of Padova, Italy. E-mail campione{at}bio.unipd.it

The Pitx2 gene regulates left-right (L/R) asymmetrical cardiac morphogenesis. Constitutive Pitx2 knock out (ko) mice die before birth and display, among other defects, right atrial isomerism, atrial and ventricular septal defects, and double outlet right ventricle. The myocardial role of the gene has not been dissected. In particular, how Pitx2 regulates the differential L/R cardiac identity program is not clear. Additionally, the relation between Pitx2 ko ventricular defects and the gene expression pattern is not understood. In this article we analyze Pitx2 myocardial function during mouse heart development. By in situ hybridization analysis we show that myocardial Pitx2 expression delineates the remodeling of the left atrioventricular canal, the inner curvature, the ventral part of the interventricular ring, and the ventral portion of the right and left ventricle. By genetic analysis using an allelic series of Pitx2 mutants, among which a myocardial specific ko (ko_myo) we show it has a crucial role in this process. Pitx2 ko_myo mutants survive to adulthood, when they present strong cardiac morphological and functional defects. Confocal analysis of embryonic Pitx2 ko_myo hearts reveals delayed cardiomyocyte development in the ventricular but not in the atrial Pitx2 null areas. Conversely, selective left atrial BMP10 mRNA downregulation which normally occurs at fetal stages is not found in the Pitx2 ko_myo mice. This is the first evidence for distinct Pitx2 action in mediating L/R atrial identity and asymmetrical ventricular remodeling.

Key Words: Pitx2 • heart development • conditional transgenic mouse • BMP10 • cardiomyocyte maturation

Related Article:

Pitx2: A Challenging Teenager

Robert E. Poelmann, Monique R.M. Jongbloed, and Adriana C. Gittenberger-de Groot
Circ. Res. 2008 102: 749-751. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. C. Body, C. D. Collard, S. K. Shernan, A. A. Fox, K.-Y. Liu, M. D. Ritchie, T. E. Perry, J. D. Muehlschlegel, S. Aranki, B. S. Donahue, et al. Variation in the 4q25 Chromosomal Locus Predicts Atrial Fibrillation After Coronary Artery Bypass Graft Surgery Circ Cardiovasc Genet, October 1, 2009; 2(5): 499 - 506. [Abstract] [Full Text] [PDF]

				C. A. MacRae Symptoms in Atrial Fibrillation: Why Keep Score? Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 215 - 217. [Full Text] [PDF]

				B. J.D. Boukens, V. M. Christoffels, R. Coronel, and A. F.M. Moorman Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias Circ. Res., January 2, 2009; 104(1): 19 - 31. [Abstract] [Full Text] [PDF]

				R. E. Poelmann, M. R.M. Jongbloed, and A. C. Gittenberger-de Groot Pitx2: A Challenging Teenager Circ. Res., April 11, 2008; 102(7): 749 - 751. [Full Text] [PDF]