Skip to main content
SpringerLink
Log in

Transcription factor Pitx3 mutant mice as a model for Parkinson’s disease

  • Review
  • Published:
Frontiers in Biology

Abstract

BACKGROUND

Parkinson’s disease (PD) is a common, age-dependent degenerative neurological disorder impairing motor control function and cognition. A key pathology of PD is a degeneration of the nigrostriatal dopamine system, leading to a severe dopamine denervation in the striatum and dynsfunction of the striatal neural circuits.

OBJECTIVE

To better understand the pathophysiology of the nigrostriatal dopamine denervation and to discover better treatments, animal PD models are needed.

METHODS

The authors’ original research on the transcription factor Pitx3 null mutant mice and the relevant literature were reviewed.

RESULTS

An important feature of an animal PD model is the severe, PD-like nigrostriatal dopamine denervation. This feature is provided in the transcription factor Pitx3 null mutant mice. These mice have a severe and bilateral nigral dopamine neuron loss and dopamine denervation in the dorsal striatum, while the dopamine neuron loss in the ventral tegmental area and dopamine denervation in the ventral striatum are moderate, creating a dorsal-ventral dopamine loss gradient and mimicking the dopamine denervation pattern in PD. Pitx3 null mice show motor function deficits in the balance beam and pole tests and these deficits are reversed by L-3,4-dihydroxyphenylalanine (L-dopa). These mice also show impaired cognitive functions as indicated by reduced motor learning and avoidance memory. L-dopa, D1 agonists and, to a lesser extent, D2 agonists, induce normal horizontal movements (walking) and also dyskinesia-like movements consisting of vertical body trunk movements and waving paw movements.

CONCLUSION

The easy-to-maintain Pitx3 null mice with an autogenic, consistent and gradient dopamine denervation are a convenient and suitable mouse model to study the consequences of dopamine loss in PD and to test dopaminergic replacement therapies for PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, Burn D, Barone P, Pagonabarraga J, Allcock L, Santangelo G, Foltynie T, Janvin C, Larsen J P, Barker R A, Emre M (2010). Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology, 75(12): 1062–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aarsland D, Kurz M W (2010). The epidemiology of dementia associated with Parkinson disease. J Neurol Sci, 289 (1-2): 18–22

    Article  PubMed  Google Scholar 

  • Alexander G E, De Long M R, Strick P L (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci, 9(1): 357–381

    Article  CAS  PubMed  Google Scholar 

  • Ardayfio P, Moon J, Leung K K, Youn-Hwang D, Kim K S (2008). Impaired learning and memory in Pitx3 deficient aphakia mice: a genetic model for striatum-dependent cognitive symptoms in Parkinson’s disease. Neurobiol Dis, 31(3): 406–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bagga V, Dunnett S B, Fricker R A (2015). The 6-OHDA mouse model of Parkinson’s disease-Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions. Behav Brain Res, 288: 107–117

    Article  CAS  PubMed  Google Scholar 

  • Ballard P A, Tetrud J W, Langston J W (1985). Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology, 35(7): 949–956

    Article  CAS  PubMed  Google Scholar 

  • Bastide M F, Meissner W G, Picconi B, Fasano S, Fernagut P O, Feyder M, Francardo V, Alcacer C, Ding Y, Brambilla R, Fisone G, Jon Stoessl A, Bourdenx M, Engeln M, Navailles S, De Deurwaerdère P, Ko W K, Simola N, Morelli M, Groc L, Rodriguez M C, Gurevich E V, Quik M, Morari M, Mellone M, Gardoni F, Tronci E, Guehl D, Tison F, Crossman A R, Kang U J, Steece-Collier K, Fox S, Carta M, Angela Cenci M, Bézard E (2015). Pathophysiology of L-dopainduced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol, 132: 96–168

    Article  CAS  PubMed  Google Scholar 

  • Bateup H S, Santini E, Shen W, Birnbaum S, Valjent E, Surmeier D J, Fisone G, Nestler E J, Greengard P (2010). Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci USA, 107(33): 14845–14850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beaulieu-Boire I, Lang A E (2015). Behavioral effects of levodopa. Mov Disord, 30(1): 90–102

    Article  CAS  PubMed  Google Scholar 

  • Beeler J A, Cao Z F, Kheirbek M A, Zhuang X (2009). Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway. Neuropsychopharmacology, 34(5): 1149–1161

    Article  CAS  PubMed  Google Scholar 

  • Bidinost C, Matsumoto M, Chung D, Salem N, Zhang K, Stockton DW, Khoury A, Megarbane A, Bejjani B A, Traboulsi E I (2006). Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest Ophthalmol Vis Sci, 47(4): 1274–1280

    Article  PubMed  Google Scholar 

  • Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004). Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res, 318(1): 121–134

    Article  PubMed  Google Scholar 

  • Carlsson A (2001). A half-century of neurotransmitter research: impact on neurology and psychiatry. Nobel lecture. Biosci Rep, 21(6): 691–710

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Xie Z, Turkson S, Zhuang X (2015). A53T human -synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J Neurosci, 35: 890–905

    Article  PubMed  CAS  Google Scholar 

  • Chesselet MF, Richter F (2011). Modelling of Parkinson’s disease in mice. Lancet Neurol, 10: 1108–18

    Article  PubMed  Google Scholar 

  • Chiken S, Sato A, Ohta C, Kurokawa M, Arai S, Maeshima J, Sunayama-Morita T, Sasaoka T, Nambu A (2015). Dopamine D1 receptor-mediated transmission maintains information flow through the cortico-striato-entopeduncular direct pathway to release movements. Cereb Cortex, 25: 4885–97

    Article  PubMed  PubMed Central  Google Scholar 

  • Chu H Y, Atherton J F, Wokosin D, Surmeier D J, Bevan M D (2015). Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron, 85(2): 364–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coelho M, Ferreira J J (2012). Late-stage Parkinson disease. Nat Rev Neurol, 8 (8):435–42

    CAS  PubMed  Google Scholar 

  • Cools R, Barker R A, Sahakian B J, Robbins T W (2001). Mechanisms of cognitive set flexibility in Parkinson’s disease. Brain, 124: 2503–2512

    Article  CAS  PubMed  Google Scholar 

  • Ciliax B J, Drash G W, Staley J K, Haber S, Mobley C J, Miller G W, Mufson E J, Mash D C, Levey A I (1999). Immunocytochemical localization of the dopamine transporter in human brain. J Comp Neurol, 409(1): 38–56

    Article  CAS  PubMed  Google Scholar 

  • Damier P, Hirsch E C, Agid Y, Graybiel A M (1999). The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain, 122 (Pt 8): 1437–1448

    PubMed  Google Scholar 

  • Darvas M, Palmiter R D (2009). Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors. Proc Natl Acad Sci USA, 106(34): 14664–14669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Lau LM, Breteler MM (2006). Epidemiology of Parkinson’s disease. Lancet Neurol, 5(6): 525–535

    Article  PubMed  Google Scholar 

  • Del Tredici K, Braak H (2016). Review: Sporadic Parkinson’s disease: development and distribution of a-synuclein pathology. Neuropathol Appl Neurobiol, 42(1): 33–50

    Article  PubMed  CAS  Google Scholar 

  • Deng Y, Lanciego J, Kerkerian-Le-Goff L, Coulon P, Salin P, Kachidian P, Lei W, Del Mar N, Reiner A (2015). Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats. Front Syst Neurosci, 9: 51

    PubMed  PubMed Central  Google Scholar 

  • Ding S, Li L, Zhou F M (2015). Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output. J Neurophysiol, 113(6): 1697–1711

    Article  CAS  PubMed  Google Scholar 

  • Ding Y, Restrepo J, Won L, Hwang D Y, Kim K S, Kang U J (2007). Chronic 3,4-dihydroxyphenylalanine treatment induces dyskinesia in aphakia mice, a novel genetic model of Parkinson’s disease. Neurobiol Dis, 27(1): 11–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Y, Won L, Britt J P, Lim S A, McGehee D S, Kang U J (2011). Enhanced striatal cholinergic neuronal activity mediates L-DOPAinduced dyskinesia in parkinsonian mice. Proc Natl Acad Sci USA, 108(2): 840–845

    Article  CAS  PubMed  Google Scholar 

  • Doig N M, Moss J, Bolam J P (2010). Cortical and thalamic innervation of direct and indirect pathway medium-sized spiny neurons in mouse striatum. J Neurosci, 30(44): 14610–14618

    Article  CAS  PubMed  Google Scholar 

  • Doucet J P, Nakabeppu Y, Bedard P J, Hope B T, Nestler E J, Jasmin B J, Chen J S, Iadarola M J, St-Jean M, Wigle N, Blanchet P, Grondin R, Robertson G S (1996). Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein (s) in both the rodent and primate striatum. Eur J Neurosci, 8(2): 365–381

    Article  CAS  PubMed  Google Scholar 

  • Durieux P F, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M, Schiffmann S N, de Kerchove d’Exaerde A (2009). D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci, 12(4): 393–395

    Article  CAS  PubMed  Google Scholar 

  • Durieux P F, Schiffmann S N, de Kerchove d’Exaerde A (2012). Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J, 31(3): 640–653

    Article  CAS  PubMed  Google Scholar 

  • Ekstrand M I, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson F S, Trifunovic A, Hoffer B, Cullheim S, Mohammed A H, Olson L, Larsson N G (2007). Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA, 104(4): 1325–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fahn S (2015). The medical treatment of Parkinson disease from James Parkinson to George Cotzias. Mov Disord, 30(1): 4–18

    Article  CAS  PubMed  Google Scholar 

  • Francis T C, Chandra R, Friend D M, Finkel E, Dayrit G, Miranda J, Brooks J M, Iñiguez S D, O'Donnell P, Kravitz A, Lobo M K (2015. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry, 77: 212–22

  • Franco V, Turner R S (2012). Testing the contributions of striatal dopamine loss to the genesis of parkinsonian signs. Neurobiol Dis, 47(1): 114–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friend D M, Kravitz A V (2014). Working together: basal ganglia pathways in action selection. Trends Neurosci, 37(6): 301–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galati S, Stanzione P, D’ Angelo V, Fedele E, Marzetti F, Sancesario G, Procopio T, Stefani A (2009). The pharmacological blockade of medial forebrain bundle induces an acute pathological synchronization of the cortico-subthalamic nucleus-globus pallidus pathway. J Physiol, 587 (Pt 18): 4405–4423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gellhaar S, Marcellino D, Abrams M B, Galter D (2015). Chronic LDOPA induces hyperactivity, normalization of gait and dyskinetic behavior in MitoPark mice. Genes Brain Behav, 14(3): 260–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerfen C R, Bolam J P (2010) The neuroanatomical organization of the basal ganglia. In: Steiner H, Tseng K Y (eds). Handbook of Basal Ganglia Structure and Function. Academic Press. Pages 3–28

    Chapter  Google Scholar 

  • German D C, Manaye K F (1993). Midbrain dopaminergic neurons (nuclei A8, A9, and A10): three-dimensional reconstruction in the rat. J Comp Neurol, 331(3): 297–309

    Article  CAS  PubMed  Google Scholar 

  • Glajch K E, Fleming S M, Surmeier D J, Osten P (2012). Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson’s disease. Behav Brain Res, 230(2): 309–316

    Article  CAS  PubMed  Google Scholar 

  • Glass M, Dragunow M, Faull R L (2000). The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA (A) receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience, 97(3): 505–519

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, SpillantiniMG, Del Tredici K, Braak H (2013). 100 years of Lewy pathology. Nat Rev Neurol, 9(1): 13–24

    Article  CAS  PubMed  Google Scholar 

  • Golden J P, Demaro J A, Knoten A, Hoshi M, Pehek E, Johnson EM Jr, Gereau R W, Jain S (2013). Dopamine-dependent compensation maintains motor behavior in mice with developmental ablation of dopaminergic neurons. J Neurosci, 33(43): 17095–17107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gotham A M, Brown R G, Marsden C D (1988). ‘Frontal’ cognitive function in patients with Parkinson’s disease ‘on’ and ‘off’ levodopa. Brain, 111 (Pt 2): 299–321

    Article  PubMed  Google Scholar 

  • Graybiel A M, Grafton S T (2015). The striatum: where skills and habits meet. Cold Spring Harb Perspect Biol, 7 (8): a021691

    Article  PubMed  CAS  Google Scholar 

  • Guo Y, Le W D, Jankovic J, Yang H R, Xu H B, Xie W J, Song Z, Deng H (2011). Systematic genetic analysis of the PITX3 gene in patients with Parkinson disease. Mov Disord, 26(9): 1729–1732

    Article  PubMed  Google Scholar 

  • Haber S N (2016). Corticostriatal circuitry. Dialogues Clin Neurosci, 18(1): 7–21

    PubMed  PubMed Central  Google Scholar 

  • Haber S N, Knutson B (2010). The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology, 35(1): 4–26

    Article  PubMed  Google Scholar 

  • Hardman C D, Henderson J M, Finkelstein D I, Horne M K, Paxinos G, Halliday G M (2002). Comparison of the basal ganglia in rats, marmosets, macaques, baboons, and humans: volume and neuronal number for the output, internal relay, and striatal modulating nuclei. J Comp Neurol, 445(3): 238–255

    Article  PubMed  Google Scholar 

  • Hikosaka O, Takikawa Y, Kawagoe R (2000). Role of the basal ganglia in the control of purposive saccadic eye movements. Physiol Rev, 80(3): 953–978

    CAS  PubMed  Google Scholar 

  • Hornykiewicz O (1998). Biochemical aspects of Parkinson’s disease. Neurology, 51 (2 Suppl 2): S2–S9

    Article  CAS  PubMed  Google Scholar 

  • Hornykiewicz O (2001). Chemical neuroanatomy of the basal ganglia— normal and in Parkinson’s disease. J Chem Neuroanat, 22 (1-2): 3–12

    Article  CAS  PubMed  Google Scholar 

  • Huerta-Ocampo I, Mena-Segovia J, Bolam J P (2014). Convergence of cortical and thalamic input to direct and indirect pathway medium spiny neurons in the striatum. Brain Struct Funct, 219(5): 1787–1800

    Article  PubMed  Google Scholar 

  • Hurd Y L, Suzuki M, Sedvall G C (2001). D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. J Chem Neuroanat, 22 (1-2): 127–137

    Article  CAS  PubMed  Google Scholar 

  • Hwang D Y, Ardayfio P, Kang U J, Semina E V, Kim K S (2003). Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res, 114(2): 123–131

    Article  CAS  PubMed  Google Scholar 

  • Hwang D Y, Fleming S M, Ardayfio P, Moran-Gates T, Kim H, Tarazi F I, Chesselet M F, Kim K S (2005). 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson’s disease. J Neurosci, 25(8): 2132–2137

    Article  CAS  PubMed  Google Scholar 

  • Ikemoto S, Yang C, Tan A (2015). Basal ganglia circuit loops, dopamine and motivation: A review and enquiry. Behav Brain Res, 290: 17–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiménez-Jiménez F J, García-Martín E, Alonso-Navarro H, Agúndez J A (2014). PITX3 and risk for Parkinson’s disease: a systematic review and meta-analysis. Eur Neurol,71 (1–2):49–56

  • Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees A J, the Parkinson’s Disease Research Group of the United Kingdom (2008). Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology, 71(7): 474–480

    Article  CAS  PubMed  Google Scholar 

  • Kirik D, Rosenblad C, Björklund A (1998). Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6- hydroxydopamine in the rat. Exp Neurol, 152(2): 259–277

    Article  CAS  PubMed  Google Scholar 

  • Kish S J, Shannak K, Hornykiewicz O (1988). Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N Engl J Med, 318(14): 876–880

    Article  CAS  PubMed  Google Scholar 

  • Kita H, Kita T (2011). Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia. J Neurosci, 31(28): 10311–10322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kordower J H, Olanow C W, Dodiya H B, Chu Y, Beach T G, Adler C H, Halliday G M, Bartus R T (2013). Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain, 136 (Pt 8): 2419–2431

    Article  PubMed  PubMed Central  Google Scholar 

  • Korotkova T M, Ponomarenko A A, Haas H L, Sergeeva O A (2005). Differential expression of the homeobox gene Pitx3 in midbrain dopaminergic neurons. Eur J Neurosci. 22: 1287–93

    Article  PubMed  Google Scholar 

  • Kravitz A V, Freeze B S, Parker P R, Kay K, Thwin M T, Deisseroth K, Kreitzer A C (2010). Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature, 466(7306): 622–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lane E L, Cheetham S C, Jenner P (2006). Does contraversive circling in the 6-OHDA-lesioned rat indicate an ability to induce motor complications as well as therapeutic effects in Parkinson’s disease? Exp Neurol, 197(2): 284–290

    Article  CAS  PubMed  Google Scholar 

  • Le W, Zhang L, Xie W, Li S, Dani J A (2015). Pitx3 deficiency produces decreased dopamine signaling and induces motor deficits in Pitx3 (-/-) mice. Neurobiol Aging, 36(12): 3314–3320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee C S, Sauer H, Bjorklund A (1996). Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat. Neuroscience, 72(3): 641–653

    Article  CAS  PubMed  Google Scholar 

  • Lees A J, Tolosa E, Olanow C W (2015). Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr. Mov Disord, 30(1): 19–36

    Article  CAS  PubMed  Google Scholar 

  • Lemos J C, Friend D M, Kaplan A R, Shin J H, Rubinstein M, Kravitz A V, Alvarez V A (2016). Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling. Neuron, 90(4): 824–838

    Article  CAS  PubMed  Google Scholar 

  • Levey A I, Hersch S M, Rye D B, Sunahara R K, Niznik H B, Kitt C A, Price D L, Maggio R, Brann M R, Ciliax B J (1993). Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci U S A. 90: 8861–8865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis D A, Melchitzky D S, Sesack S R, Whitehead R E, Auh S, Sampson A (2001). Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol, 432(1): 119–136

    Article  CAS  PubMed  Google Scholar 

  • Li L, Qiu G, Ding S, Zhou F M (2013). Serotonin hyperinnervation and upregulated 5-HT2A receptor expression and motor-stimulating function in nigrostriatal dopamine-deficient Pitx3 mutant mice. Brain Res, 1491: 236–250

    Article  CAS  PubMed  Google Scholar 

  • Li L, Zhou F M (2013). Parallel dopamine D1 receptor activity dependence of l-Dopa-induced normal movement and dyskinesia in mice. Neuroscience, 236: 66–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lobo M K, Zaman S, Damez-Werno D M, Koo JW, Bagot R C, Di Nieri J A, Nugent A, Finkel E, Chaudhury D, Chandra R, Riberio E, Rabkin J, Mouzon E, Cachope R, Cheer J F, Han M H, Dietz D M, Self D W, Hurd Y L, Vialou V, Nestler E J (2013). DFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli. J Neurosci, 33(47): 18381–18395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luk K C, Rymar V V, van den Munckhof P, Nicolau S, Steriade C, Bifsha P, Drouin J, Sadikot A F (2013). The transcription factor Pitx3 is expressed selectively in midbrain dopaminergic neurons susceptible to neurodegenerative stress. J Neurochem, 125(6): 932–943

    Article  CAS  PubMed  Google Scholar 

  • Marin C, Rodriguez-Oroz M C, Obeso J A (2006). Motor complications in Parkinson’s disease and the clinical significance of rotational behavior in the rat: have we wasted our time? Exp Neurol, 197(2): 269–274

    Article  CAS  PubMed  Google Scholar 

  • Matsuda W, Furuta T, Nakamura K C, Hioki H, Fujiyama F, Arai R, Kaneko T (2009). Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci, 29(2): 444–453

    Article  CAS  PubMed  Google Scholar 

  • McCann H, Cartwright H, Halliday G M (2016). Neuropathology of a- synuclein propagation and braak hypothesis. Mov Disord, 31(2): 152–160

    Article  CAS  PubMed  Google Scholar 

  • McRitchie D A, Cartwright H R, Halliday G M (1997). Specific A10 dopaminergic nuclei in the midbrain degenerate in Parkinson’s disease. Exp Neurol, 144(1): 202–213

    Article  CAS  PubMed  Google Scholar 

  • Mitchell I J, Cooper A J, Griffiths M R (1999). The selective vulnerability of striatopallidal neurons. Prog Neurobiol, 59(6): 691–719

    Article  CAS  PubMed  Google Scholar 

  • Nambu A (2008). Seven problems on the basal ganglia. Curr Opin Neurobiol, 18(6): 595–604

    Article  CAS  PubMed  Google Scholar 

  • Nambu A (2011). Somatotopic organization of the primate Basal Ganglia. Front Neuroanat, 5: 26

    Article  PubMed  PubMed Central  Google Scholar 

  • Nelson E L, Liang C L, Sinton C M, German D C (1996). Midbrain dopaminergic neurons in the mouse: computer-assisted mapping. J Comp Neurol, 369(3): 361–371

    Article  CAS  PubMed  Google Scholar 

  • Nunes I, Tovmasian L T, Silva RM, Burke R E, Goff S P (2003). Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci USA, 100(7): 4245–4250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nutt J G, Chung K A, Holford N H (2010). Dyskinesia and the antiparkinsonian response always temporally coincide: a retrospective study. Neurology, 74(15): 1191–1197

    Article  PubMed  PubMed Central  Google Scholar 

  • Obeso J A, Rodriguez-Oroz M C, Stamelou M, Bhatia K P, Burn D J (2014). The expanding universe of disorders of the basal ganglia. Lancet, 384(9942): 523–531

    Article  PubMed  Google Scholar 

  • Olanow CW, SternMB, Sethi K (2009). The scientific and clinical basis for the treatment of Parkinson disease (2009. Neurology, 72 (21 Suppl 4): S1–S136

    Article  PubMed  Google Scholar 

  • Oorschot D E (1996). Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: a stereological study using the cavalieri and optical disector methods. J Comp Neurol, 366(4): 580–599

    Article  CAS  PubMed  Google Scholar 

  • Oorschot D E (2010). Cell types in the different nuclei of the basal ganglia. In: Steiner H, Tseng K Y (Eds.), Handbook of Basal Ganglia Structure and Function. London: Academic Press, pp. 63–74

    Chapter  Google Scholar 

  • Parkinson J (1817). An essay on shaking palsy. Originally published by Sherwood, Neely, and Jones (London, 1817), reprinted in J Neuropsychiatry Clin Neurosci. 2002 Spring; 14: 223–36

    Google Scholar 

  • Redgrave P, Rodriguez M, Smith Y, Rodriguez-Oroz M C, Lehericy S, Bergman H, Agid Y, De Long M R, Obeso J A (2010). Goal-directed and habitual control in the basal ganglia: implications for Parkinson’s disease. Nat Rev Neurosci, 11(11): 760–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Révy D, Jaouen F, Salin P, Melon C, Chabbert D, Tafi E, Concetta L, Langa F, Amalric M, Kerkerian-Le Goff L, Marie H, Beurrier C (2014). Cellular and behavioral outcomes of dorsal striatonigral neuron ablation: new insights into striatal functions. Neuropsychopharmacology, 39(11): 2662–2672

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reyes S, Fu Y, Double K L, Cottam V, Thompson L H, Kirik D, Paxinos G, Watson C, Cooper H M, Halliday G M (2013). Trophic factors differentiate dopamine neurons vulnerable to Parkinson’s disease. Neurobiol Aging, 34(3): 873–886

    Article  CAS  PubMed  Google Scholar 

  • Robbins TW, Cools R (2014). Cognitive deficits in Parkinson’s disease: a cognitive neuroscience perspective. Mov Disord, 29(5): 597–607

    Article  PubMed  Google Scholar 

  • Rothwell P E, Fuccillo M V, Maxeiner S, Hayton S J, Gokce O, Lim B K, Fowler S C, Malenka R C, Südhof T C (2014). Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell, 158(1): 198–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samii A, Nutt J G, Ransom B R (2004). Parkinson’s disease. Lancet, 363(9423): 1783–1793

    Article  CAS  PubMed  Google Scholar 

  • Sano H, Chiken S, Hikida T, Kobayashi K, Nambu A (2013). Signals through the striatopallidal indirect pathway stop movements by phasic excitation in the substantia nigra. J Neurosci, 33(17): 7583–7594

    Article  CAS  PubMed  Google Scholar 

  • Sano H, Yasoshima Y, Matsushita N, Kaneko T, Kohno K, Pastan I, Kobayashi K (2003). Conditional ablation of striatal neuronal types containing dopamine D2 receptor disturbs coordination of basal ganglia function. J Neurosci, 23(27): 9078–9088

    CAS  PubMed  Google Scholar 

  • Schwarting R K, Huston J P (1996). The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol, 50 (2-3): 275–331

    CAS  PubMed  Google Scholar 

  • Semina E V, Ferrell R E, Mintz-Hittner H A, Bitoun P, Alward W L, Reiter R S, Funkhauser C, Daack-Hirsch S, Murray J C (1998). A novel homeobox gene PITX3 is mutated in families with autosomaldominant cataracts and ASMD. Nat Genet, 19(2): 167–170

    Article  CAS  PubMed  Google Scholar 

  • Semina E V, Murray J C, Reiter R, Hrstka R F, Graw J (2000). Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum Mol Genet, 9(11): 1575–1585

    Article  CAS  PubMed  Google Scholar 

  • Semina E V, Reiter R S, Murray J C (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(12): 2109–2116

    Article  CAS  PubMed  Google Scholar 

  • Sesack S R, Grace A A (2010). Cortico-Basal Ganglia reward network: microcircuitry. Neuropsychopharmacology, 35(1): 27–47

    Article  PubMed  Google Scholar 

  • Siepel F J, Brønnick K S, Booij J, Ravina B M, Lebedev A V, Pereira J B, Grüner R, Aarsland D (2014). Cognitive executive impairment and dopaminergic deficits in de novo Parkinson’s disease. Mov Disord, 29(14): 1802–1808

    Article  CAS  PubMed  Google Scholar 

  • Simpson E H, Kellendonk C, Kandel E (2010). A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron, 65(5): 585–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smidt M P, Smits S M, Bouwmeester H, Hamers F P, van der Linden A J, Hellemons A J, Graw J, Burbach J P (2004). Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development, 131(5): 1145–1155

    Article  CAS  PubMed  Google Scholar 

  • Smidt M P, Van Schaick H S, Lanctôt C, Tremblay J J, Cox J J, van der Kleij A A, Wolterink G, Drouin J, Burbach J P (1997). A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci U S A. 94: 13305–13310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith Y, Galvan A, Ellender T J, Doig N, Villalba RM, Huerta-Ocampo I, Wichmann T, Bolam J P (2014). The thalamostriatal system in normal and diseased states. Front Syst Neurosci, 8: 5

    PubMed  PubMed Central  Google Scholar 

  • Smits S M, Burbach J P, Smidt M P (2006). Developmental origin and fate of meso-diencephalic dopamine neurons. Prog Neurobiol, 78(1): 1–16

    Article  CAS  PubMed  Google Scholar 

  • Stern Y, Langston J W (1985). Intellectual changes in patients with MPTP-induced parkinsonism. Neurology, 35(10): 1506–1509

    Article  CAS  PubMed  Google Scholar 

  • Stern Y, Tetrud J W, Martin W R, Kutner S J, Langston J W (1990). Cognitive change following MPTP exposure. Neurology, 40(2): 261–264

    Article  CAS  PubMed  Google Scholar 

  • Svenningsson P, Westman E, Ballard C, Aarsland D (2012). Cognitive impairment in patients with Parkinson’s disease: diagnosis, biomarkers, and treatment. Lancet Neurol, 11(8): 697–707

    Article  PubMed  Google Scholar 

  • Thiele S L, Warre R, Khademullah C S, Fahana N, Lo C, Lam D, Talwar S, Johnston T H, Brotchie J M, Nash J E (2011). Generation of a model of L-DOPA-induced dyskinesia in two different mouse strains. J Neurosci Methods, 197(2): 193–208

    Article  CAS  PubMed  Google Scholar 

  • Tremblay L, Worbe Y, Thobois S, Sgambato-Faure V, Féger J (2015). Selective dysfunction of basal ganglia subterritories: From movement to behavioral disorders. Mov Disord, 30(9): 1155–1170

    Article  PubMed  Google Scholar 

  • Ungerstedt U (1971). Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl, 367 (S367): 95–122

    Article  CAS  PubMed  Google Scholar 

  • van den Munckhof P, Luk K C, Ste-Marie L, Montgomery J, Blanchet P J, Sadikot A F, Drouin J (2003). Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development, 130(11): 2535–2542

    Article  PubMed  CAS  Google Scholar 

  • van den Munckhof P, Gilbert F, Chamberland M, Lévesque D, Drouin J. (2006). Striatal neuroadaptation and rescue of locomotor deficit by L-dopa in aphakia mice, a model of Parkinson's disease. J Neurochem, 96(1): 160–170

    Article  PubMed  CAS  Google Scholar 

  • Varnum D S, Stevens L C (1968). Aphakia, a new mutation in the mouse. J Hered, 59(2): 147–150

    CAS  PubMed  Google Scholar 

  • Walker F O (2007). Huntington’s disease. Lancet, 369(9557): 218–228

    Article  CAS  PubMed  Google Scholar 

  • Wei W, Li L, Yu G, Ding S, Li C, Zhou F M (2013). Supersensitive presynaptic dopamine D2 receptor inhibition of the striatopallidal projection in nigrostriatal dopamine-deficient mice. J Neurophysiol, 110(9): 2203–2216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weintraub D, Simuni T, Caspell-Garcia C, Coffey C, Lasch S, Siderowf A, Aarsland D, Barone P, Burn D, Chahine LM, Eberling J, Espay A J, Foster E D, Leverenz J B, Litvan I, Richard I, Troyer M D, Hawkins K A, and the Parkinson’s Progression Markers Initiative (2015). Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson’s disease. Mov Disord, 30(7): 919–927

    Article  PubMed  PubMed Central  Google Scholar 

  • Willard A M, Bouchard R S, Gittis A H (2015). Differential degradation of motor deficits during gradual dopamine depletion with 6- hydroxydopamine in mice. Neuroscience, 301: 254–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yarnall A J, Breen D P, Duncan G W, Khoo T K, Coleman S Y, Firbank M J, Nombela C, Winder-Rhodes S, Evans J R, Rowe J B, Mollenhauer B, Kruse N, Hudson G, Chinnery P F, O’Brien J T, Robbins T W, Wesnes K, Brooks D J, Barker R A, Burn D J, and the ICICLE-PD Study Group (2014). Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. Neurology, 82(4): 308–316

    Article  PubMed  PubMed Central  Google Scholar 

  • Yung K K, Bolam J P, Smith A D, Hersch S M, Ciliax B J, Levey A I (1995). Immunocytochemical localization of D1 and D2 dopamine receptors in the basal ganglia of the rat: light and electron microscopy. Neuroscience, 65(3): 709–730

    Article  CAS  PubMed  Google Scholar 

  • Zhou F M (2016). The Substantia Nigra Pars Reticulata. In: Steiner H, Tseng K (eds.). Handbook of Basal Ganglia Structure and Function. pp. 293–316. Elsevier.

    Google Scholar 

  • Zhou Q Y, Palmiter R D (1995). Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell, 83(7): 1197–1209

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH grants R01NS097671 and R03NS085380 to FMZ and R01NS21229 and R01DA09411 to JAD.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Tennessee College of Medicine, Memphis, TN, 38103, USA

    Fu-Ming Zhou & Li Li

  2. Department of Pathology, University of Tennessee College of Medicine, Memphis, TN, 38103, USA

    Juming Yue

  3. Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John A. Dani

Authors
  1. Fu-Ming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juming Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John A. Dani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fu-Ming Zhou.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, FM., Li, L., Yue, J. et al. Transcription factor Pitx3 mutant mice as a model for Parkinson’s disease. Front. Biol. 11, 427–438 (2016). https://doi.org/10.1007/s11515-016-1429-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-016-1429-8

Keywords

Search

Navigation