{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T05:19:57Z","timestamp":1792732797986,"version":"4.5.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"6","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,2,5]]},"abstract":"<jats:p>\n                    Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional\n                    <jats:italic>Nurr1<\/jats:italic>\n                    gene-targeted mice in which\n                    <jats:italic>Nurr1<\/jats:italic>\n                    is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that\n                    <jats:italic>Nurr1<\/jats:italic>\n                    ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that\n                    <jats:italic>Nurr1<\/jats:italic>\n                    ablation in mice recapitulates early features of Parkinson's disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1221077110","type":"journal-article","created":{"date-parts":[[2013,1,23]],"date-time":"2013-01-23T02:27:25Z","timestamp":1358908045000},"page":"2360-2365","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":167,"title":["Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons"],"prefix":"10.1073","volume":"110","author":[{"given":"Banafsheh","family":"Kadkhodaei","sequence":"first","affiliation":[{"name":"Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Alvarsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Schintu","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ramsk\u00f6ld","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Volakakis","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza","family":"Joodmardi","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yoshitake","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, SE-17177 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kehr","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, SE-17177 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mickael","family":"Decressac","sequence":"additional","affiliation":[{"name":"Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, SE-22184 Lund, Sweden; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Bj\u00f6rklund","sequence":"additional","affiliation":[{"name":"Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, SE-22184 Lund, Sweden; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rickard","family":"Sandberg","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm, Sweden;"},{"name":"Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Svenningsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Perlmann","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research Ltd, Stockholm Branch, SE-17177 Stockholm, Sweden;"},{"name":"Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,1,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nature08533","article-title":"Forcing cells to change lineages","volume":"462","author":"Graf T","year":"2009","unstructured":"T Graf, T Enver, Forcing cells to change lineages. Nature 462, 587\u2013594 (2009).","journal-title":"Nature"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nrg3209","article-title":"Maintaining differentiated cellular identity","volume":"13","author":"Holmberg J","year":"2012","unstructured":"J Holmberg, T Perlmann, Maintaining differentiated cellular identity. Nat Rev Genet 13, 429\u2013439 (2012).","journal-title":"Nat Rev Genet"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1146\/annurev-cellbio-092910-154226","article-title":"Regulation of terminal differentiation programs in the nervous system","volume":"27","author":"Hobert O","year":"2011","unstructured":"O Hobert, Regulation of terminal differentiation programs in the nervous system. Annu Rev Cell Dev Biol 27, 681\u2013696 (2011).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1002\/ana.21995","article-title":"Clinical progression in Parkinson disease and the neurobiology of axons","volume":"67","author":"Cheng H-C","year":"2010","unstructured":"H-C Cheng, CM Ulane, RE Burke, Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67, 715\u2013725 (2010).","journal-title":"Ann Neurol"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nature01645","article-title":"Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors","volume":"423","author":"Wang Z","year":"2003","unstructured":"Z Wang, et al., Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423, 555\u2013560 (2003).","journal-title":"Nature"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s00441-004-0974-7","article-title":"Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells","volume":"318","author":"Perlmann T","year":"2004","unstructured":"T Perlmann, A Wall\u00e9n-Mackenzie, Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells. Cell Tissue Res 318, 45\u201352 (2004).","journal-title":"Cell Tissue Res"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1126\/science.276.5310.248","article-title":"Dopamine neuron agenesis in Nurr1-deficient mice","volume":"276","author":"Zetterstr\u00f6m RH","year":"1997","unstructured":"RH Zetterstr\u00f6m, et al., Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248\u2013250 (1997).","journal-title":"Science"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"4013","DOI":"10.1073\/pnas.95.7.4013","article-title":"Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons","volume":"95","author":"Saucedo-Cardenas O","year":"1998","unstructured":"O Saucedo-Cardenas, et al., Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci USA 95, 4013\u20134018 (1998).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1006\/mcne.1998.0673","article-title":"Dopamine biosynthesis is selectively abolished in substantia nigra\/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene","volume":"11","author":"Castillo SO","year":"1998","unstructured":"SO Castillo, et al., Dopamine biosynthesis is selectively abolished in substantia nigra\/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol Cell Neurosci 11, 36\u201346 (1998).","journal-title":"Mol Cell Neurosci"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1046\/j.1471-4159.1999.02218.x","article-title":"Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury","volume":"73","author":"Le W","year":"1999","unstructured":"W Le, OM Conneely, Y He, J Jankovic, SH Appel, Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J Neurochem 73, 2218\u20132221 (1999).","journal-title":"J Neurochem"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1002\/mds.20820","article-title":"Translated mutation in the Nurr1 gene as a cause for Parkinson\u2019s disease","volume":"21","author":"Grimes DA","year":"2006","unstructured":"DA Grimes, et al., Translated mutation in the Nurr1 gene as a cause for Parkinson\u2019s disease. Mov Disord 21, 906\u2013909 (2006).","journal-title":"Mov Disord"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1212\/WNL.58.6.881","article-title":"Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson\u2019s disease","volume":"58","author":"Xu P-Y","year":"2002","unstructured":"P-Y Xu, et al., Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson\u2019s disease. Neurology 58, 881\u2013884 (2002).","journal-title":"Neurology"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1001\/archneur.60.5.722","article-title":"A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease","volume":"60","author":"Zheng K","year":"2003","unstructured":"K Zheng, B Heydari, DK Simon, A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease. Arch Neurol 60, 722\u2013725 (2003).","journal-title":"Arch Neurol"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1002\/cne.20828","article-title":"Nurr1 in Parkinson\u2019s disease and related disorders","volume":"494","author":"Chu Y","year":"2006","unstructured":"Y Chu, et al., Nurr1 in Parkinson\u2019s disease and related disorders. J Comp Neurol 494, 495\u2013514 (2006).","journal-title":"J Comp Neurol"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1111\/j.1468-1331.2011.03644.x","article-title":"Decreased NURR1 and PITX3 gene expression in Chinese patients with Parkinson\u2019s disease","volume":"19","author":"Liu H","year":"2012","unstructured":"H Liu, et al., Decreased NURR1 and PITX3 gene expression in Chinese patients with Parkinson\u2019s disease. Eur J Neurol 19, 870\u2013875 (2012).","journal-title":"Eur J Neurol"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"3229","DOI":"10.1242\/dev.01128","article-title":"Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons","volume":"131","author":"Alb\u00e9ri L","year":"2004","unstructured":"L Alb\u00e9ri, P Sgad\u00f2, HH Simon, Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons. Development 131, 3229\u20133236 (2004).","journal-title":"Development"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"e325","DOI":"10.1371\/journal.pbio.0050325","article-title":"The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age","volume":"5","author":"Kittappa R","year":"2007","unstructured":"R Kittappa, WW Chang, RB Awatramani, RDG McKay, The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol 5, e325 (2007).","journal-title":"PLoS Biol"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"15923","DOI":"10.1523\/JNEUROSCI.3910-09.2009","article-title":"Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons","volume":"29","author":"Kadkhodaei B","year":"2009","unstructured":"B Kadkhodaei, et al., Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29, 15923\u201315932 (2009).","journal-title":"J Neurosci"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.neuron.2008.07.010","article-title":"Glutamate receptors on dopamine neurons control the persistence of cocaine seeking","volume":"59","author":"Engblom D","year":"2008","unstructured":"D Engblom, et al., Glutamate receptors on dopamine neurons control the persistence of cocaine seeking. Neuron 59, 497\u2013508 (2008).","journal-title":"Neuron"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nbt.2282","article-title":"Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells","volume":"30","author":"Ramsk\u00f6ld D","year":"2012","unstructured":"D Ramsk\u00f6ld, et al., Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. Nat Biotechnol 30, 777\u2013782 (2012).","journal-title":"Nat Biotechnol"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders S","year":"2010","unstructured":"S Anders, W Huber, Differential expression analysis for sequence count data. Genome Biol 11, R106 (2010).","journal-title":"Genome Biol"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"W305-11","DOI":"10.1093\/nar\/gkp427","article-title":"ToppGene Suite for gene list enrichment analysis and candidate gene prioritization","volume":"37","author":"Chen J","year":"2009","unstructured":"J Chen, EE Bardes, BJ Aronow, AG Jegga, ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 37, W305-11 (2009).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00702-009-0187-z","article-title":"Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk for Parkinson\u2019s disease?","volume":"116","author":"Bergman O","year":"2009","unstructured":"O Bergman, et al., Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk for Parkinson\u2019s disease? J Neural Transm 116, 333\u2013338 (2009).","journal-title":"J Neural Transm"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.neurobiolaging.2008.03.008","article-title":"PITX3 polymorphism is associated with early-onset Parkinson\u2019s disease","volume":"31","author":"Bergman O","year":"2010","unstructured":"O Bergman, et al., PITX3 polymorphism is associated with early-onset Parkinson\u2019s disease. Neurobiol Aging 31, 114\u2013117 (2010).","journal-title":"Neurobiol Aging"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.neurobiolaging.2009.02.015","article-title":"Association of transcription factor polymorphisms PITX3 and EN1 with Parkinson\u2019s disease","volume":"32","author":"Haubenberger D","year":"2011","unstructured":"D Haubenberger, et al., Association of transcription factor polymorphisms PITX3 and EN1 with Parkinson\u2019s disease. Neurobiol Aging 32, 302\u2013307 (2011).","journal-title":"Neurobiol Aging"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jns.2012.02.025","article-title":"Meta-analysis of association between PITX3 gene polymorphism and Parkinson\u2019s disease","volume":"317","author":"Tang L","year":"2012","unstructured":"L Tang, et al., Meta-analysis of association between PITX3 gene polymorphism and Parkinson\u2019s disease. J Neurol Sci 317, 80\u201386 (2012).","journal-title":"J Neurol Sci"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1093\/hmg\/ddl243","article-title":"Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity","volume":"15","author":"Kontopoulos E","year":"2006","unstructured":"E Kontopoulos, JD Parvin, MB Feany, Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15, 3012\u20133023 (2006).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"8465","DOI":"10.1021\/bi0341152","article-title":"Nuclear localization of alpha-synuclein and its interaction with histones","volume":"42","author":"Goers J","year":"2003","unstructured":"J Goers, et al., Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42, 8465\u20138471 (2003).","journal-title":"Biochemistry"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.neuroscience.2009.03.002","article-title":"Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice","volume":"160","author":"Schell H","year":"2009","unstructured":"H Schell, T Hasegawa, M Neumann, PJ Kahle, Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice. Neuroscience 160, 796\u2013804 (2009).","journal-title":"Neuroscience"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/ana.410260409","article-title":"Striatal dopamine deficiency in Parkinson\u2019s disease: role of aging","volume":"26","author":"Scherman D","year":"1989","unstructured":"D Scherman, et al., Striatal dopamine deficiency in Parkinson\u2019s disease: role of aging. Ann Neurol 26, 551\u2013557 (1989).","journal-title":"Ann Neurol"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1523\/JNEUROSCI.04-11-02866.1984","article-title":"The control of firing pattern in nigral dopamine neurons: Single spike firing","volume":"4","author":"Grace AA","year":"1984","unstructured":"AA Grace, BS Bunney, The control of firing pattern in nigral dopamine neurons: Single spike firing. J Neurosci 4, 2866\u20132876 (1984).","journal-title":"J Neurosci"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.bbabio.2010.11.016","article-title":"Regional variation in mitochondrial DNA copy number in mouse brain","volume":"1807","author":"Fuke S","year":"2011","unstructured":"S Fuke, M Kubota-Sakashita, T Kasahara, Y Shigeyoshi, T Kato, Regional variation in mitochondrial DNA copy number in mouse brain. BBA Bioenergetics 1807, 270\u2013274 (2011).","journal-title":"BBA Bioenergetics"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/5007","article-title":"Generalized lacZ expression with the ROSA26 Cre reporter strain","volume":"21","author":"Soriano P","year":"1999","unstructured":"P Soriano, Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21, 70\u201371 (1999).","journal-title":"Nat Genet"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1221077110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T23:10:21Z","timestamp":1714864221000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1221077110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,22]]},"references-count":33,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2013,2,5]]}},"alternative-id":["10.1073\/pnas.1221077110"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1221077110","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,22]]},"assertion":[{"value":"2013-01-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}