{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:41:33Z","timestamp":1791265293049,"version":"4.1.0"},"reference-count":38,"publisher":"The Company of Biologists","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,6,1]]},"abstract":"<jats:p>Mesencephalic dopaminergic (MesDA) neurons play crucial roles in motor and behavioral processes; their loss in Parkinson's disease (PD) results in striatal dopamine (DA) deficiency and hypokinetic movement disorder. The Pitx3 homeobox gene is expressed in the MesDA system. 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. Similar to human PD, dorsal SN neurons (which are Pitx3 negative) are spared in mutant mice. Thus, Pitx3 defines a pathway for survival of neurons that are implicated in PD and that are required for spontaneous locomotor activity.<\/jats:p>","DOI":"10.1242\/dev.00464","type":"journal-article","created":{"date-parts":[[2003,4,17]],"date-time":"2003-04-17T16:48:41Z","timestamp":1050598121000},"page":"2535-2542","source":"Crossref","is-referenced-by-count":254,"title":["Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons"],"prefix":"10.1242","volume":"130","author":[{"given":"Pepijn","family":"van den Munckhof","sequence":"first","affiliation":[{"name":"Unite\u0301 de recherche en ge\u0301ne\u0301tique mole\u0301culaire,Institut de recherches cliniques de Montre\u0301al (IRCM), Montre\u0301al,QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin C.","family":"Luk","sequence":"additional","affiliation":[{"name":"Cone Laboratory, Department of Neurology and Neurosurgery, Montre\u0301al Neurological Institute, McGill University, Montre\u0301al, QC H3A 2B4,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line","family":"Ste-Marie","sequence":"additional","affiliation":[{"name":"Laboratoire de neurobiologie, Centre de recherche, CHUM Ho\u0302pital Notre-Dame, Universite\u0301 de Montre\u0301al, Montre\u0301al QC H2L 4M1,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Laboratoire de neurobiologie, Centre de recherche, CHUM Ho\u0302pital Notre-Dame, Universite\u0301 de Montre\u0301al, Montre\u0301al QC H2L 4M1,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre J.","family":"Blanchet","sequence":"additional","affiliation":[{"name":"Centre de recherche, CHUM Ho\u0302pital Saint-Luc, Universite\u0301 de Montre\u0301al, Montre\u0301al QC H2X 3J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas F.","family":"Sadikot","sequence":"additional","affiliation":[{"name":"Cone Laboratory, Department of Neurology and Neurosurgery, Montre\u0301al Neurological Institute, McGill University, Montre\u0301al, QC H3A 2B4,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Drouin","sequence":"additional","affiliation":[{"name":"Unite\u0301 de recherche en ge\u0301ne\u0301tique mole\u0301culaire,Institut de recherches cliniques de Montre\u0301al (IRCM), Montre\u0301al,QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042604282433800_REF1","doi-asserted-by":"crossref","unstructured":"Amendt, B. A., Sutherland, L. B., Semina, E. V. and Russo, A. F. (1998). The molecular basis of Rieger syndrome. analysis of Pitx2 homeodomain protein activities. J. Biol. Chem.273,20066-20072.","DOI":"10.1074\/jbc.273.32.20066"},{"key":"2021042604282433800_REF2","doi-asserted-by":"crossref","unstructured":"Bayer, S. A., Wills, K. V., Triarhou, L. C., Verina, T., Thomas,J. D. and\n          Ghetti, B. (1995). Selective vulnerability of late-generated dopaminergic neurons of the substantia nigra in weaver mutant mice. Proc. Natl. Acad. Sci. USA92,9137-9140.","DOI":"10.1073\/pnas.92.20.9137"},{"key":"2021042604282433800_REF3","unstructured":"Bjo\u0308rklund, A. and Lindvall, O., eds(1984). Dopamine containing systems in the CNS. In Handbook of Chemical Neuroanatomy, pp.55-122. Amsterdam: Elsevier."},{"key":"2021042604282433800_REF4","doi-asserted-by":"crossref","unstructured":"Chen, H., Lun, Y., Ovchinnikov, D., Kokubo, H., Oberg, K. C.,Pepicelli,\n          C. V., Gan, L., Lee, B. and Johnson, R. L.(1998). Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat. Genet.19,51-55.","DOI":"10.1038\/ng0598-51"},{"key":"2021042604282433800_REF5","doi-asserted-by":"crossref","unstructured":"Dawson, T., Mandir, A. and Lee, M. (2002). Animal models of PD: pieces of the same puzzle? Neuron35,219-222.","DOI":"10.1016\/S0896-6273(02)00780-8"},{"key":"2021042604282433800_REF6","doi-asserted-by":"crossref","unstructured":"Egan, M. F. and Weinberger, D. R. (1997). Neurobiology of schizophrenia. Curr. Opin. Neurobiol.7, 701-707.","DOI":"10.1016\/S0959-4388(97)80092-X"},{"key":"2021042604282433800_REF7","doi-asserted-by":"crossref","unstructured":"Fearnley, J. M. and Lees, A. J. (1991). Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain114,2283-2301.","DOI":"10.1093\/brain\/114.5.2283"},{"key":"2021042604282433800_REF8","unstructured":"Franklin, K. B. J. and Paxinos, G. (1997). The Mouse Brain in Stereotaxic Coordinates. New York:Academic Press."},{"key":"2021042604282433800_REF9","doi-asserted-by":"crossref","unstructured":"Hynes, M. and Rosenthal, A. (1999). Specification of dopaminergic and serotonergic neurons in the vertebrate CNS. Curr. Neurol.9,26-36.","DOI":"10.1016\/S0959-4388(99)80004-X"},{"key":"2021042604282433800_REF10","doi-asserted-by":"crossref","unstructured":"Jackson-Lewis, V., Vila, M., Djaldetti, R., Guegan, C.,Liberatore, G., Liu,\n          J., O'Malley, K. L., Burke, R. E. and Przedborski,S. (2000). Developmental cell death in dopaminergic neurons of the substantia nigra of mice. J. Comp Neurol.424,476-488.","DOI":"10.1002\/1096-9861(20000828)424:3<476::AID-CNE6>3.0.CO;2-0"},{"key":"2021042604282433800_REF11","unstructured":"Jellinger, K. A. (2001). The pathology of Parkinson's disease. In Parkinson's Disease: Advances in Neurology. Vol. 86 (ed. D. Calne and S. Calne), pp. 55-72. Philadelphia, PA: Lippincott,Williams and Wilkins.."},{"key":"2021042604282433800_REF12","doi-asserted-by":"crossref","unstructured":"King, D. P., Zhao, Y., Sangoram, A. M., Wilsbacher, L. D.,Tanaka, M.,\n          Antoch, M. P., Steeves, T. D., Vitaterna, M. H.,Kornhauser, J. M., Lowrey, P. L., Turek, F. W. and Takahashi, J. S.(1997). Positional cloning of the mouse circadian clock gene. Cell89,641-653.","DOI":"10.1016\/S0092-8674(00)80245-7"},{"key":"2021042604282433800_REF13","doi-asserted-by":"crossref","unstructured":"Kish, S. J., Shannak, K. and Hornykiewicz, O.(1988). Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. New Engl. J. Med.318,876-880.","DOI":"10.1056\/NEJM198804073181402"},{"key":"2021042604282433800_REF14","doi-asserted-by":"crossref","unstructured":"Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura,Y.,\n          Minoshima, S., Yokochi, M., Mizuno, Y. and Shimizu, N.(1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature392,605-608.","DOI":"10.1038\/33416"},{"key":"2021042604282433800_REF15","doi-asserted-by":"crossref","unstructured":"Lebel, M., Gauthier, Y., Moreau, A. and Drouin, J.(2001). Pitx3 activates mouse tyrosine hydroxylase promoter via a high affinity binding site. J. Neurochem.76, 1-11.","DOI":"10.1046\/j.1471-4159.2001.00257.x"},{"key":"2021042604282433800_REF16","doi-asserted-by":"crossref","unstructured":"Montgomery, E. B., Jr, Baker, K. B., Lyons, K. and Koller, W. C. (1999). Abnormal performance on the PD test battery by asymptomatic first-degree relatives. Neurology52,757-762.","DOI":"10.1212\/WNL.52.4.757"},{"key":"2021042604282433800_REF17","doi-asserted-by":"crossref","unstructured":"Piccini, P., Burn, D. J., Ceravolo, R., Maraganore, D. and Brooks, D. J. (1999). The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann. Neurol.45,577-582.","DOI":"10.1002\/1531-8249(199905)45:5<577::AID-ANA5>3.0.CO;2-O"},{"key":"2021042604282433800_REF18","doi-asserted-by":"crossref","unstructured":"Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E.,Dehejia, A.,\n          Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R. et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science276,2045-2047.","DOI":"10.1126\/science.276.5321.2045"},{"key":"2021042604282433800_REF19","doi-asserted-by":"crossref","unstructured":"Rieger, D. K., Reichenberger, E., McLean, W., Sidow, A. and Olsen, B. R. (2001). A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice. Genomics72,61-72.","DOI":"10.1006\/geno.2000.6464"},{"key":"2021042604282433800_REF20","doi-asserted-by":"crossref","unstructured":"Saucedo-Cardenas, O., Quintana-Hau, J. D., Le, W. D., Smidt, M. P., Cox,\n          J. J., DeMayo, F., Burbach, J. P. H. and Conneely, O. M.(1998). Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc. Natl. Acad. Sci. USA95,4013-4018.","DOI":"10.1073\/pnas.95.7.4013"},{"key":"2021042604282433800_REF21","doi-asserted-by":"crossref","unstructured":"Semina, E. V., Reiter, R. S. and Murray, J.(1997). Isolation of a new homeobox gene belonging to the Pitx\/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum. Mol. Genet.6,2109-2116.","DOI":"10.1093\/hmg\/6.12.2109"},{"key":"2021042604282433800_REF22","doi-asserted-by":"crossref","unstructured":"Semina, E. V., Ferrell, R. E., Mintz-Hittner, H. A., Bitoun, P.,Alward, W.\n          L. M., Reiter, R. S., Funkhauser, C., Daack-Hirsch, S. and Murray, J. C. (1998). A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nat. Genet.19,167-170.","DOI":"10.1038\/527"},{"key":"2021042604282433800_REF23","doi-asserted-by":"crossref","unstructured":"Semina, E. V., Murray, J. C., Reiter, R. and Hrstka, R. F. G. J. (2000). Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum. Mol. Genet.9,1575-1585.","DOI":"10.1093\/hmg\/9.11.1575"},{"key":"2021042604282433800_REF24","doi-asserted-by":"crossref","unstructured":"Smidt, M., van, Schaick, H. S. A., Lancto\u0302t, C., Tremblay,J. J., Cox, J. J., van, der, Kleij, A. A. M., Wolterink, G., Drouin, J. and Burbach, P. H. (1997). A homeodomain gene PTX3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc. Natl. Acad. Sci. USA94,13305-13310.","DOI":"10.1073\/pnas.94.24.13305"},{"key":"2021042604282433800_REF25","doi-asserted-by":"crossref","unstructured":"Smidt, M. P., Asbreuk, C. H., Cox, J. J., Chen, H. and Johnson,R. L. (2000). A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat. Neurosci.3,337-341.","DOI":"10.1038\/73902"},{"key":"2021042604282433800_REF26","doi-asserted-by":"crossref","unstructured":"Ste-Marie, L., Vachon, L., Bemeur, C., Lambert, J. and Montgomery, J. (1999). Local striatal infusion of MPP+ does not result in increased hydroxylation after systemic administration of 4-hydroxybenzoate. Free Radic. Biol. Med.27,997-1007.","DOI":"10.1016\/S0891-5849(99)00170-7"},{"key":"2021042604282433800_REF27","doi-asserted-by":"crossref","unstructured":"Sveinbjornsdottir, S., Hicks, A. A., Jonsson, T., Petursson,H.,\n          Gugmundsson, G., Frigge, M. L., Kong, A., Gulcher, J. R. and Stefansson, K. (2000). Familial aggregation of Parkinson's disease in Iceland. New Engl. J. Med.343,1765-1770.","DOI":"10.1056\/NEJM200012143432404"},{"key":"2021042604282433800_REF28","doi-asserted-by":"crossref","unstructured":"Swanson, D. J., Zellmer, E. and Lewis, E. J.(1998). AP1 proteins mediate the cAMP response of the dopamine beta-hydroxylase gene. J. Biol. Chem.273,24065-24074.","DOI":"10.1074\/jbc.273.37.24065"},{"key":"2021042604282433800_REF29","doi-asserted-by":"crossref","unstructured":"Tanner, C. M., Ottman, R., Goldman, S. M., Ellenberg, J., Chan,P.,\n          Mayeux, R. and Langston, J. W. (1999). Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc.281,341-346.","DOI":"10.1001\/jama.281.4.341"},{"key":"2021042604282433800_REF30","doi-asserted-by":"crossref","unstructured":"Tvrdik, P., Asadi, A., Kozak, L. P., Nedergaard, J., Cannon, B. and\n          Jacobsson, A. (1997). Cig30, a mouse member of a novel membrane protein gene family, is involved in the recruitment of brown adipose tissue. J. Biol. Chem.272,31738-31746.","DOI":"10.1074\/jbc.272.50.31738"},{"key":"2021042604282433800_REF31","doi-asserted-by":"crossref","unstructured":"Varnum, D. S. and Stevens, L. C. (1968). Aphakia, a new mutation in the mouse. J. Hered.59,147-150.","DOI":"10.1093\/oxfordjournals.jhered.a107667"},{"key":"2021042604282433800_REF32","doi-asserted-by":"crossref","unstructured":"West, M. J. (1993). New stereological methods for counting neurons. Neurobiol. Aging14,275-285.","DOI":"10.1016\/0197-4580(93)90112-O"},{"key":"2021042604282433800_REF33","doi-asserted-by":"crossref","unstructured":"West, M. J. and Gundersen, H. J. (1990). Unbiased stereological estimation of the number of neurons in the human hippocampus. J. Comp Neurol.296, 1-22.","DOI":"10.1002\/cne.902960102"},{"key":"2021042604282433800_REF34","doi-asserted-by":"crossref","unstructured":"Witta, J., Baffi, J. S., Palkovits, M., Mezey, E., Castillo, S. O. and Nikodem,\n          V. M. (2000). Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation. Mol. Brain Res.84,67-78.","DOI":"10.1016\/S0169-328X(00)00211-4"},{"key":"2021042604282433800_REF35","doi-asserted-by":"crossref","unstructured":"Ye, W., Shimamura, K., Rubenstein, J. L., Hynes, M. A. and Rosenthal,\n          A. (1998). FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell93,755-766.","DOI":"10.1016\/S0092-8674(00)81437-3"},{"key":"2021042604282433800_REF36","doi-asserted-by":"crossref","unstructured":"Zetterstrom, R. H., Williams, R., Perlmann, T. and Olson, L.(1996). Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Mol Brain Res41,111-120.","DOI":"10.1016\/0169-328X(96)00074-5"},{"key":"2021042604282433800_REF37","doi-asserted-by":"crossref","unstructured":"Zetterstrom, R. H., Solomin, L., Jansson, L., Hoffer, B. J.,Olson, L. and\n          Perlmann, T. (1997). Dopamine neuron agenesis in Nurr1-deficient mice. Science276,248-250.","DOI":"10.1126\/science.276.5310.248"},{"key":"2021042604282433800_REF38","doi-asserted-by":"crossref","unstructured":"Zheng, B., Albrecht, U., Kaasik, K., Sage, M., Lu, W., Vaishnav,S., Li, Q.,\n          Sun, Z. S., Eichele, G., Bradley, A. and Lee, C. C.(2001). Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell105,683-694.","DOI":"10.1016\/S0092-8674(01)00380-4"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/130\/11\/2535\/1143202\/2535.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/130\/11\/2535\/1143202\/2535.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T05:10:21Z","timestamp":1619413821000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/130\/11\/2535\/41944\/Pitx3-is-required-for-motor-activity-and-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,6,1]]},"references-count":38,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2003,6,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.00464","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2003,6,1]]}}}