Disease relevance of Pitx3

• Pitx3 was mapped close to aphakia on mouse chromosome 19 [1].
• 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson's disease [2].
• Although no Ptx3 gene expression could be detected in these tissues, Ptx1 presented with a quite ubiquitous pattern of distribution, being expressed at quite constant levels in normal tissues and in all 60 pituitary tumors analyzed [3].

Psychiatry related information on Pitx3

• Thus, Pitx3 defines a pathway for survival of neurons that are implicated in PD and that are required for spontaneous locomotor activity [4].

High impact information on Pitx3

• Further expression analysis of Pitx3 in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs [5].
• Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype [6].
• Pitx3 is required for development of substantia nigra dopaminergic neurons [7].
• These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system [7].
• These lines of evidence suggest that the abnormal ocular development in the aphakia mouse is due to the deletion upstream of the Pitx3 gene [8].

Chemical compound and disease context of Pitx3

• We now show that only a subset of MesDA neurons express Pitx3 and that in Pitx3-deficient aphakia mice, this subset is progressively lost by apoptosis during fetal (substantia nigra, SN) and postnatal (ventral tegmental area) development, resulting in very low striatal DA and akinesia [4].

Biological context of Pitx3

• The aphakia homozygous mouse is characterized by small eyes lacking a lens, which fail to develop beyond 11 d.p.c. These data make Pitx3 a strong candidate gene for the aphakia phenotype in the mouse and suggest a role for the human homolog in congenital lens malformations [1].
• The expression of Pitx3 in the brain is restricted to the mesDA system and the gene is induced relatively late, at E11.5, a time when tyrosine hydroxylase (Th) gene expression is initiated [9].
• Recent studies of mouse mutant aphakia have implicated the homeobox gene Pitx3 in the survival of substantia nigra dopaminergic neurons, the degeneration of which causes Parkinson's disease [10].
• Pitx3 activates mouse tyrosine hydroxylase promoter via a high-affinity binding site [11].
• Our results differ in that we find not only the distant intergenic deletion, but also a much larger deletion directly in the Pitx3 gene, eliminating exon 1 and extending into intron 1 and the promoter region [12].

Anatomical context of Pitx3

• Furthermore, they also expressed other midbrain DA markers, including Nurr1 and Pitx3, and released significant amounts of DA [13].
• Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3 [9].
• We investigated to what extent Pitx3 deficiency, causing hyperdopaminergic transmission in the nucleus accumbens microcircuitry, may lead to developmental changes [14].
• In the central nervous system, Pitx3-directed GFP was visualized in dopaminergic (DA) neurons in the substantia nigra and ventral tegmental area [15].
• Combined simultaneous expression of Nurr1 and Pitx3 however did not lead to enhancement of tyrosine hydroxylase expression over that of either factor alone in either of the cell lines or with either method [16].

Regulatory relationships of Pitx3

• Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development [10].

Other interactions of Pitx3

• Cig30 and Pitx3 genes are arranged in a partially overlapping tail-to-tail array resulting in complementary transcripts [17].
• A recent report described a deletion in the intergenic region between Gbf1 and Pitx3 as the possible ak mutation [12].
• Noteworthy, the Lmx1b expression domain is shared by Ptx2 in posterior hypothalamic regions and by Ptx3 in the dopaminergic neurons of the ventral midbrain [18].
• First, early events will be influenced by genes coding for transcription factors like Pax6, Pitx3, Maf or Sox [19].

Analytical, diagnostic and therapeutic context of Pitx3

• Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures [6].
• Additionally, Pitx3 transcripts were not detected in the ak/ak mice either in the lens placode or at later developmental stages of the lens by in situ hybridization [8].
• Furthermore, real-time PCR analyses of in vitro differentiated Pitx3-expressing ES cells revealed that genes highly expressed in A9 DA neurons were up-regulated [20].

References