Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons.
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.
van den Munckhof
Pepijn
P
Unité de recherche en génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
Luk
Kelvin C
KC
Ste-Marie
Line
L
Montgomery
Jane
J
Blanchet
Pierre J
PJ
Sadikot
Abbas F
AF
Drouin
Jacques
J
D000818:Animals; D001035:Aphakia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D002470:Cell Survival; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine