we have highlighted herein our current knowledge on the role of pitx2 in the developing and adult heart as well as on the state - of - the - art link between pitx2 and af . several studies have shown that pitx2 is essential for pulmonary vein development ( mommersteeg et al . , 2007 ) , a highly recurrent pro - arrhythmogenic region in humans . experimental evidence has shown that pitx2 is important for transcriptional regulation in the secondary heart field ( ai et al . , 2006 ) , , additional evidence has revealed a role of pitx2 in the regulation of cell - to - cell communication proteins and essential ion channels , which modulate critical aspects of the cardiac action potential , as well as a role repressing the sinoatrial node gene program ( wang et al . , 2010 ; chinchilla et al . , 2011 ; kirchhof et al . , overall , these data strongly implicate pitx2 as an upstream regulator of pro - arrhythmogenic events . however , there are several missing links . the first one is how the identified genetic variants alter pitx2 expression and to date , this point remains unanswered . secondly , it remains elusive how altered pitx2 expression would modify conductive elements leading to the onset of af ( although new insights have progressively being gained ; figure 1 ) , in particular whether the impaired conductive elements might be deregulated already from embryonic stages , as suggested by wang et al . ( 2012 ) or exclusively in the fetal / adult heart as reported by kirchhof et al . , it might be postulated that impaired pitx2 in the developing heart might be a predisposing factor for af . however , an early defect in pitx2 function would be expected to have severe consequences for cardiac embryogenesis , and thus it is more likely that fetal or adult dysfunction might underlie pitx2 predisposition to af . in addition , it is unclear if pitx2 deficiency might also lead to impaired formation and/or function of other components of the ventricular cardiac conduction system such as the av node and the left and right av bundle branches . right mutant mouse model iv / iv suggests that left / right cues can influence av node formation ( franco and icardo , 2001 ) . nonetheless , further studies are required to demonstrate a putative role of pitx2 in ventricular conduction system deployment . interestingly , in addition to reports linking 4q25 risk variants to af , new gwas have identified several other genetic variants highly associated with af , which are located at 9p21 , 1q21 , and 16q22 , respectively . on chromosome 9p21 , no candidate gene has been linked to af , and thus its relevance awaits further experimental and functional evidence ( larson et al . , 2007 ) . however , genetic variants at 1q21 are linked to kcnn3 ( ellinor et al . , 2011 ) and il6r ( schnabel et al . , 2011 ) , respectively whereas risk genetic variants at 16q22 are linked to zfhx3 ( gudbjartsson et al . , 2009 ) . to date it remains elusive the putative involvement of these genes in the pathophysiology of af . thus , further insights are required to explore both the links between all gwas associated genes as well as the cellular and molecular mechanisms that might underlie a functional role between kcnn3 , il6r and zfhx3 , and af , yet this aspect remains to be elucidated . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
pitx2 is a homeobox transcription factor involved in left 
 right signaling during embryogenesis . 
 disruption of left 
 right signaling in mice within its core nodal / lefty cascade , results in impaired expression of the last effector of the left 
 right cascade , pitx2 , leading in many cases to absence or bilateral expression of pitx2 in lateral plate mesoderm ( lpm ) . 
 loss of pitx2 expression in lpm results in severe cardiac malformations , including right cardiac isomerism . 
 pitx2 is firstly expressed asymmetrically in the left but not right lpm , before the cardiac crescent forms , and subsequently , as the heart develops , becomes confined to the left side of the linear heart tube . 
 expression of pitx2 is remodeled during cardiac looping , becoming localized to the ventral portion of the developing ventricular chambers , while maintaining a distinct left - sided atrial expression . 
 the importance of pitx2 during cardiogenesis has been illustrated by the complex and robust cardiac defects observed on systemic deletion of pitx2 in mice . 
 lack of pitx2 expression leads to embryonic lethality at mid - term , and pitx2-deficient embryos display isomeric hearts with incomplete closure of the body wall . 
 however , whereas the pivotal role of pitx2 during cardiogenesis is well sustained , its putative role in the fetal and adult heart is largely unexplored . 
 recent genome - wide association studies have identified several genetic variants highly associated with atrial fibrillation ( af ) . among them 
 are genetic variants located on chromosome 4q25 adjacent to pitx2 . 
 since then several transgenic approaches have provided evidences of the role of the homeobox transcription factor pitx2 and atrial arrhythmias . 
 here , we review new insights into the cellular and molecular links between pitx2 and af .