Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs.
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.
Tessari
Alessandra
A
CNR Institute of Neurosciences, Department of Biomedical Sciences, University of Padova, Italy.
Pietrobon
Mara
M
Notte
Antonella
A
Cifelli
Giuseppe
G
Gage
Philip J
PJ
Schneider
Michael D
MD
Lembo
Giuseppe
G
Campione
Marina
M
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006325:Heart Atria / Q000196:embryology* / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000473:pathology; D006352:Heart Ventricles / Q000196:embryology* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012849:Sinoatrial Node / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*; D000097577:Homeobox Protein PITX2
D019485:Bone Morphogenetic Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C119152:Bmp10 protein, mouse; C484469:Nkx2-5 protein, mouse