Disease relevance of Pitx2

• We show that these sites specifically bind to Pitx2 protein in vitro and that in transfected neuroblastoma cells, the Pitx2 binding sites contribute to the basal activity of the Gad1 promoter [1].
• Further, dysgenesis of the Pitx2(-)(/)(-) extraocular muscle and thickening of the mesothelial layer of cornea were observed in the ocular system where Pitx2 is expressed symmetrically, and these resulted in enophthalmos [2].
• The corneal hypertrophy also resembles the corneal hypertrophy of Pitx2-/- mice [3].
• Pitx2 and cardiac development: a molecular link between left/right signaling and congenital heart disease [4].
• The pattern of expression of the Ptx2 gene among the different subsets of pituitary adenomas was even more varied [5].

Psychiatry related information on Pitx2

• In the Fmr1 knockout mice, a model for fragile X mental retardation syndrome, the levels of regulator of G-protein signaling (Rgs) 4 but not Rgs2 mRNA were considerably reduced (65% from control) in the cerebral cortex and hippocampal CA1 region [6].

High impact information on Pitx2

• Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway [7].
• CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic hearts, and they activate Pitx2c transcription in transient transfection assays [7].
• Regulated exchange of HDAC1/beta-catenin converts Pitx2 from repressor to activator, analogous to control of TCF/LEF1 [8].
• Here, we report that the bicoid-related transcription factor Pitx2 is rapidly induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes [8].
• Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction [8].

Biological context of Pitx2

• The lack of lefty-1 resulted in bilateral expression of nodal, lefty-2, and Pitx2 (a homeobox gene normally expressed on the left side) [9].
• Pitx2 encodes a transcription factor expressed throughout the left lateral plate mesoderm and subsequently on the left side of asymmetric organs such as the heart and gut during organogenesis in the chick embryo [10].
• Moreover, our results uncover a new function of Pitx2 in regulation of cell motility in craniofacial development [11].
• Nodal gene expression in the node was initiated in cryptic mutant mice, but neither nodal, lefty-2 nor Pitx2 were expressed in the left lateral plate mesoderm [12].
• In this study, we analyzed Pitx2 mRNA and PITX2 protein expression in individual cells of the developing e10.5-e14.5 mouse CNS using multiple markers of cellular proliferation and differentiation [13].

Anatomical context of Pitx2

• We report that Pitx2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved in determination of L-R asymmetry in both mouse and chick [14].
• Expression of Pitx2 and plexin A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural crest development during outflow tract formation [15].
• We show that Pitx2 isoforms have interchangeable functions in branchial arches and that Pitx2 target pathways respond to small changes in total Pitx2 dose [11].
• Pitx2, a paired-related homeobox gene that encodes multiple isoforms, is the gene mutated in the haploinsufficient Rieger Syndrome type 1 that includes dental, ocular and abdominal wall anomalies as cardinal features [11].
• Lef-1 is expressed in the dental epithelium after Pitx2, and both factors have overlapping expression patterns in the tooth bud and cap stages [16].

Associations of Pitx2 with chemical compounds

• We previously reported expression patterns and function of Pitx2c in the generation of laterality and asymmetric morphogenesis of heart and gastro-intestinal tract in mouse, frog and zebrafish (Development 126 (1999) 1225; Mech. Dev. 90 (2000) 41) [17].
• This suggests that retinoic acid may be an important inductive signal which regulates the developmental and tissue-specific expression of Ptx2 [18].
• Genetic or pharmacological inactivation of the dopamine D1 receptor differentially alters the expression of regulator of G-protein signalling (Rgs) transcripts [19].

Physical interactions of Pitx2

• An enhancer located between exons 4 and 5 in which a putative T-half site was identified near an Nkx2.5-binding site regulates asymmetric expression of Pitx2 [20].

Regulatory relationships of Pitx2

• These results indicate that Pitx2 may regulate Gad1 expression in mammals, suggesting a new role for this key developmental transcription factor as a regulator of GABAergic differentiation during mammalian neural development [1].
• Misexpression experiments demonstrate that Shh and nodal positively regulate Pitx2 expression [21].
• Ptx1 is expressed in most pituitary-derived cell lines and as is the related Ptx2 (Rieger) gene [22].
• The Wnt/beta-catenin pathway rapidly induces the transcription of the cell-type-restricted transcription factor Pitx2 that is required for effective cell-specific proliferation activating growth-regulating genes [23].

Other interactions of Pitx2

• Expression of early heart determination factors is not altered in mutants, and the defect in heart looping does not appear to involve the Nodal/Lefty/Pitx2 pathway [24].
• On the left side, Shh induces nodal expression in lateral plate mesoderm (LPM); nodal in turn upregulates left-sided expression of the bicoid-like homeobox gene Pitx2 [4] [5] [6] [25].
• In this study, we examined the expression and regulation of Pitx1 and Pitx2 during mouse tooth development [26].
• By contrast, Bone morphogenetic 4 (Bmp4) and Pitx2 are specifically expressed in the mesenchyme of the cecal bud at E11 [27].
• Bead implantation experiments demonstrate that ectopic expression of Fgf8 can induce/maintain the expression of both Pitx1 and Pitx2 at E9 [26].

Analytical, diagnostic and therapeutic context of Pitx2

• Our analysis of Pitx2-/- mutant mice showed reduced Lef-1 expression in facial tissues by RT-PCR and quantitative RT-PCR [16].
• In this report we demonstrate a 32-kDa polypeptide on Western blots of nuclear extracts from a rat pituitary cell line, using a Pitx2 specific antibody (designated P2R10) [28].
• In situ hybridization studies in Tbx1(-/-) mouse embryos revealed downregulation of Pitx2 in these cells [20].
• METHODS: We examined the fetal livers of mouse embryos with homozygous disruption of the Pitx2 gene, using flow cytometry immunophenotyping analysis, as well as immunohistochemistry techniques [29].
• Scanning electron microscopy (SEM) and OCT measurements of reference films correlated closely (r = 0.9995) and subsequent OCT analysis of murine eyes revealed a significant reduction in CCT in Pitx2(+/-) compared with wild-type littermates (Pitx2(+/-): mean, 72 mum; range, 57-87, n = 6; wt: mean, 88 mum; range, 63-100; n = 6, P = 0.035, t-test) [30].

References