The sequential activation of transcription factors is fundamental for proper development of dopaminergic neurons. Among those the Pitx3 factor is involved in the differentiation of midbrain dopaminergic progenitors into mature neurons in mammals. Interestingly, in the brain, Pitx3 expression is restricted to mesencephalic neurons and is a fundamental factor for the expression, among others, of the tyrosine hydroxylase (TH), the Vesicular Monoamine Transporter (VMAT2) and the Dopamine Transporter (DAT) genes, which characterize dopaminergic neurons. Pitx3 is also necessary for maintaining midbrain expression of these genes in adulthood.

Extra-neural expression of Pitx3 is observed in the eye, where the factor is involved in proper development of the lens.

The Pitx3 gene has been mapped to the aphakia region on chromosome 19.  Mouse aphakia (ak/ak mouse) is a naturally occurring phenotype that develops in a specific mouse strain (129/Sv-SIJ) characterized by the development of small eye that lack a lens. Analysis has revealed that ak/ak mice have a 5’ deletion upstream of the Pitx3 gene that inhibits expression of the factor.

Although still debated, evidence suggests that, in human, polymorphism in the Pitx3 gene may be associated with a higher risk of developing Parkinson’s disease (PD), especially Early Onset PD. (PMID 21469209, PMID 19394114, PMID 24394914)