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This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. This protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein is involved in the development of the eye, tooth and abdominal organs. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Three transcript variants encoding distinct isoforms have been identified for this gene.
Pitx2 is responsible for the establishment of the left-right axis, the asymmetrical development of the heart, lungs, and spleen, twisting of the gut and stomach, as well as the development of the eyes. Once activated Pitx2 will be locally expressed in the left lateral mesoderm, tubular heart, and early gut which leads to the asymmetrical development of organs and looping of the gut. When Pitx2 is deleted, the irregular morphogenesis of organs results on the left hand side. Pitx2 is left-laterally expressed controlling the morphology of the left visceral organs. Expression of Pitx2 is controlled by an intronic enhancer ASE and Nodal. It appears that while Nodal controls cranial expression of Pitx2, ASE controls left – right expression of Pitx2, which leads to the asymmetrical development of the left sided visceral organs, such as the spleen and liver. Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells. There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions.
Pitx2 plays a role in limb myogenesis. Pitx2 can determine the development and activation of the MyoD gene (the gene responsible for skeletal myogenesis). Studies have shown that expression of Pitx2 happens before MyoD is expressed in muscles. Further studies show that Pitx2 is directly recruited to act on the MyoD core enhancer and thus, directing the expression of the MyoD gene. Pitx 2 is in a parallel pathway with Myf5 and Myf6, as both paths effect expression of MyoD. However, in the absence of the parallel pathway, Pitx2 can continue activating MyoD genes. The expression of Pitx2 saves MyoD gene expression and keeps expressing this gene for limb myogenesis. Yet, the Pitx 2 pathway is PAX3 dependent and requires this gene to enact limb myogenesis. Studies support this finding as in the absence of PAX3, there is Pitx2 expression deficit and thus, MyoD does not express itself in limb myogenesis. The Pitx2 gene is thus shown to be downstream of Pax3 and serve as an intermediate between Pax3 and MyoD. In conclusion, Pitx2 plays an integral role in limb myogenesis.
Mutations in this gene are associated with Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS), and sporadic cases of Peters anomaly. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes.
Pitx2 is overexpressed in many cancers. For example, thyroid, ovarian, and colon cancer all have higher levels of Pitx2 compared to noncancerous tissues. Scientists speculate that cancer cells improperly turn on Pitx2, leading to uncontrolled cell proliferation. This is consistent with the role of Pitx2 in regulating the growth-regulating genes cyclin D2, cyclin D1, and C-Myc.
In renal cancer, Pitx2 regulates expression of ABCB1, a multidrug transporter, by binding to the promoter region of ABCB1. Increased expression of Pitx2 in renal cancer cells is associated with increased expression of ABCB1. Thus, renal cancer cells that overexpress ABCB1 have a greater resistance to chemotherapeutic agents. In experiments where Pitx2 expression was decreased, renal cancer cells had decreased cell proliferation and greater susceptibility to doxorubicin treatment, which is consistent with other results.
In human esophageal squamous cell carcinoma (ESCC), Pitx2 is overexpressed compared to normal esophageal squamous cells. In addition, greater expression of Pitx2 is positively correlated with clinical aggressiveness of ESCC. Also, ESCC patients with high Pitx2 expression did not respond as well to definitive chemoradiotherapy (CRT) compared to ESCC patients with low Pitx2 expression. Thus, physicians may be able to use Pitx2 expression to predict how ESCC patients will respond to cancer treatment.
In Congenital Heart Disease, heterozygous mutations in Pitx2 have been involved in the development of Tetralogy of Fallot, ventricular septal defects, atrial septal defects, transposition of great arteries, and endocardial cushion defect (ECD). The mutations of the Pitx2 gene are created through alternative splicing. The isoform of Pitx2 important for cardiogenesis is Pitx2c. The lack of expression of this particular isoform correlates with these congenital defects. Pitx2 mutations significantly reduce transcriptional activity of Pitx2 and synergistic activation between Pitx2 and NKX2(also important for development of the heart). The large phenotypic spectrum due to the mutation of Pitx2 may be attributed to a variety of factors including: different genetic backgrounds, epigenetic modifiers and delayed/complete penetrance. It is important to note that the mutation of Pitx2 is not defined as the cause of these congenital heart defects, but currently perceived as a risk factor for their development.
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