Multiple Roles of Pitx2 in Cardiac Development and Disease

Abstract

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases.

In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

“…Pitx2 plays an important role in a left-sided signalling pathway that establishes the left-right asymmetry of the heart [8,9]. Pitx2 encodes 3 isoforms (Pitx2a, Pitx2b and Pitx2c) and the Pitx2c isoform promotes the embryonic development of cardiac left-right asymmetry, with levels in right and left atriums being 1:100 [10].…”

Genome-Wide Assessment of DNA Methylation in Chicken Cardiac Tissue Exposed to Different Incubation Temperatures and CO2 Levels

“…Among these, DAG1 possessed hypo-and hypermethylated CpGs, and encodes a glycoprotein that has been shown to play an important role in the inhibition of cardiomyocyte proliferation in mice (Morikawa et al, 2017). PITX2 contained an exonic CpG that was significantly hypomethylated at 38.9 • C. This gene encodes a homeobox TF with roles in heart development that have been reviewed extensively (Franco et al, 2017); of note, it has been shown to promote cardiomyocyte proliferation in mice (Tao et al, 2016). ERBB2 and ERBB4 encode receptor kinases that have been shown to promote cardiomyocyte proliferation and survival (Zhao et al, 1998).…”

Interplay between cardiac transcription factors and non-coding RNAs in predisposing to atrial fibrillation

“…PITX2 has been extensively studied, particularly its functions in heart development. It is widely recognized that PITX2C implicated in multiple pathways of cardiac left-right (L-R) asymmetry [34,35] also regulates L-R atrial identity. The phenotype of PITX2C-deficient mice is characterized by RA isomerism with two SANs at both right and left regions of sinoatrial junction, each expressing the same panel of SAN-specific molecular markers [36].…”