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Gene Review

Pitx2  -  paired-like homeodomain transcription...

Mus musculus

Synonyms: 9430085M16Rik, ALL1-responsive protein ARP1, Arp1, BRX1 homeoprotein, Brx1, ...
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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


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].


  1. Conserved function of Caenorhabditis elegans UNC-30 and mouse Pitx2 in controlling GABAergic neuron differentiation. Westmoreland, J.J., McEwen, J., Moore, B.A., Jin, Y., Condie, B.G. J. Neurosci. (2001) [Pubmed]
  2. Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Kitamura, K., Miura, H., Miyagawa-Tomita, S., Yanazawa, M., Katoh-Fukui, Y., Suzuki, R., Ohuchi, H., Suehiro, A., Motegi, Y., Nakahara, Y., Kondo, S., Yokoyama, M. Development (1999) [Pubmed]
  3. PITX2 gain-of-function in Rieger syndrome eye model. Holmberg, J., Liu, C.Y., Hjalt, T.A. Am. J. Pathol. (2004) [Pubmed]
  4. Pitx2 and cardiac development: a molecular link between left/right signaling and congenital heart disease. Campione, M., Acosta, L., Martínez, S., Icardo, J.M., Aránega, A., Franco, D. Cold Spring Harb. Symp. Quant. Biol. (2002) [Pubmed]
  5. Expression of the members of the Ptx family of transcription factors in human pituitary adenomas. Pellegrini-Bouiller, I., Manrique, C., Gunz, G., Grino, M., Zamora, A.J., Figarella-Branger, D., Grisoli, F., Jaquet, P., Enjalbert, A. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  6. Rgs4 mRNA expression is decreased in the brain of Fmr1 knockout mouse. Tervonen, T., Akerman, K., Oostra, B.A., Castrén, M. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  7. Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Bamforth, S.D., Bragança, J., Farthing, C.R., Schneider, J.E., Broadbent, C., Michell, A.C., Clarke, K., Neubauer, S., Norris, D., Brown, N.A., Anderson, R.H., Bhattacharya, S. Nat. Genet. (2004) [Pubmed]
  8. Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development. Kioussi, C., Briata, P., Baek, S.H., Rose, D.W., Hamblet, N.S., Herman, T., Ohgi, K.A., Lin, C., Gleiberman, A., Wang, J., Brault, V., Ruiz-Lozano, P., Nguyen, H.D., Kemler, R., Glass, C.K., Wynshaw-Boris, A., Rosenfeld, M.G. Cell (2002) [Pubmed]
  9. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Meno, C., Shimono, A., Saijoh, Y., Yashiro, K., Mochida, K., Ohishi, S., Noji, S., Kondoh, H., Hamada, H. Cell (1998) [Pubmed]
  10. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Logan, M., Pagán-Westphal, S.M., Smith, D.M., Paganessi, L., Tabin, C.J. Cell (1998) [Pubmed]
  11. Genetic dissection of Pitx2 in craniofacial development uncovers new functions in branchial arch morphogenesis, late aspects of tooth morphogenesis and cell migration. Liu, W., Selever, J., Lu, M.F., Martin, J.F. Development (2003) [Pubmed]
  12. A role of the cryptic gene in the correct establishment of the left-right axis. Gaio, U., Schweickert, A., Fischer, A., Garratt, A.N., Müller, T., Ozcelik, C., Lankes, W., Strehle, M., Britsch, S., Blum, M., Birchmeier, C. Curr. Biol. (1999) [Pubmed]
  13. Pitx2 distinguishes subtypes of terminally differentiated neurons in the developing mouse neuroepithelium. Martin, D.M., Skidmore, J.M., Fox, S.E., Gage, P.J., Camper, S.A. Dev. Biol. (2002) [Pubmed]
  14. Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry. Yoshioka, H., Meno, C., Koshiba, K., Sugihara, M., Itoh, H., Ishimaru, Y., Inoue, T., Ohuchi, H., Semina, E.V., Murray, J.C., Hamada, H., Noji, S. Cell (1998) [Pubmed]
  15. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Hamblet, N.S., Lijam, N., Ruiz-Lozano, P., Wang, J., Yang, Y., Luo, Z., Mei, L., Chien, K.R., Sussman, D.J., Wynshaw-Boris, A. Development (2002) [Pubmed]
  16. PITX2, beta-catenin and LEF-1 interact to synergistically regulate the LEF-1 promoter. Vadlamudi, U., Espinoza, H.M., Ganga, M., Martin, D.M., Liu, X., Engelhardt, J.F., Amendt, B.A. J. Cell. Sci. (2005) [Pubmed]
  17. Differential gene expression of Xenopus Pitx1, Pitx2b and Pitx2c during cement gland, stomodeum and pituitary development. Schweickert, A., Steinbeisser, H., Blum, M. Mech. Dev. (2001) [Pubmed]
  18. Regulated expression of the homeobox gene, rPtx2, in the developing rat. Lindberg, C., Wunderlich, M., Ratliff, J., Dinsmore, J., Jacoby, D.B. Brain Res. Dev. Brain Res. (1998) [Pubmed]
  19. Genetic or pharmacological inactivation of the dopamine D1 receptor differentially alters the expression of regulator of G-protein signalling (Rgs) transcripts. Stanwood, G.D., Parlaman, J.P., Levitt, P. Eur. J. Neurosci. (2006) [Pubmed]
  20. Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Nowotschin, S., Liao, J., Gage, P.J., Epstein, J.A., Campione, M., Morrow, B.E. Development (2006) [Pubmed]
  21. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Piedra, M.E., Icardo, J.M., Albajar, M., Rodriguez-Rey, J.C., Ros, M.A. Cell (1998) [Pubmed]
  22. The pan-pituitary activator of transcription, Ptx1 (pituitary homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3. Tremblay, J.J., Lanctôt, C., Drouin, J. Mol. Endocrinol. (1998) [Pubmed]
  23. The Wnt/beta-catenin-->Pitx2 pathway controls the turnover of Pitx2 and other unstable mRNAs. Briata, P., Ilengo, C., Corte, G., Moroni, C., Rosenfeld, M.G., Chen, C.Y., Gherzi, R. Mol. Cell (2003) [Pubmed]
  24. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Niederreither, K., Vermot, J., Messaddeq, N., Schuhbaur, B., Chambon, P., Dollé, P. Development (2001) [Pubmed]
  25. The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Schneider, A., Mijalski, T., Schlange, T., Dai, W., Overbeek, P., Arnold, H.H., Brand, T. Curr. Biol. (1999) [Pubmed]
  26. Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. St Amand, T.R., Zhang, Y., Semina, E.V., Zhao, X., Hu, Y., Nguyen, L., Murray, J.C., Chen, Y. Dev. Biol. (2000) [Pubmed]
  27. Requirement for fibroblast growth factor 10 or fibroblast growth factor receptor 2-IIIb signaling for cecal development in mouse. Burns, R.C., Fairbanks, T.J., Sala, F., De Langhe, S., Mailleux, A., Thiery, J.P., Dickson, C., Itoh, N., Warburton, D., Anderson, K.D., Bellusci, S. Dev. Biol. (2004) [Pubmed]
  28. The Pitx2 protein in mouse development. Hjalt, T.A., Semina, E.V., Amendt, B.A., Murray, J.C. Dev. Dyn. (2000) [Pubmed]
  29. Hematopoiesis following disruption of the Pitx2 homeodomain gene. Zhang, H.Z., Degar, B.A., Rogoulina, S., Resor, C., Booth, C.J., Sinning, J., Gage, P.J., Forget, B.G. Exp. Hematol. (2006) [Pubmed]
  30. Reduced human and murine corneal thickness in an axenfeld-rieger syndrome subtype. Asai-Coakwell, M., Backhouse, C., Casey, R.J., Gage, P.J., Lehmann, O.J. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
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