title: The transcription factor Pitx3 is expressed selectively in midbrain dopaminergic neurons susceptible to neurodegenerative stress.
abstract: The homeodomain transcription factor Pitx3 is critical for the survival of midbrain dopaminergic (mDA) neurons. Pitx3-deficient mice exhibit severe but selective developmental loss of mDA neurons, with accompanying locomotor deficits resembling those seen in Parkinson's disease (PD) models. Here, we identify specific mDA cell subpopulations that are consistently spared in adult Pitx3-hypomorphic (aphakia) mice, demonstrating that Pitx3 is not indiscriminately required by all mDA neurons for their survival. In aphakia mice, virtually all surviving mDA neurons in the substantia nigra (SN) and the majority of neurons in the adjacent ventral tegmental area (VTA) also express calbindin-D28k, a calcium-binding protein previously associated with resistance to injury in PD and in animal models. Cell-mapping studies in wild-type mice revealed that Pitx3 is primarily expressed in the ventral SN, a region particularly susceptible to MPTP and other dopaminergic neurotoxins. Furthermore, Pitx3-expressing SN cells are preferentially lost following MPTP treatment. Finally, SN mDA neurons in Pitx3 hemizygous mice show increased sensitivity when exposed to MPTP. Thus, SN mDA neurons are represented by at least two distinct subpopulations including MPTP-resistant Pitx3-autonomous, calbindin-positive neurons, and calbindin-negative Pitx-3-dependent cells that display elevated vulnerability to toxic injury, and probably correspond to the subpopulation that degenerates in PD. Impairment of Pitx3-dependent pathways therefore increases vulnerability of mDA neurons to toxic injury. Together, these data suggest a novel link between Pitx3 function and the selective pattern of mDA cell loss observed in PD.
authors: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors: Kelvin C
authors: KC
authors: Luk
authors: Vladimir V
authors: VV
authors: Rymar
authors: Pepijn
authors: P
authors: van den Munckhof
authors: Stefan
authors: S
authors: Nicolau
authors: Claude
authors: C
authors: Steriade
authors: Panojot
authors: P
authors: Bifsha
authors: Jacques
authors: J
authors: Drouin
authors: Abbas F
authors: AF
authors: Sadikot
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D064092:Calbindin 1; D064026:Calbindins; D002452:Cell Count; D002470:Cell Survival; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D018398:Homeodomain Proteins; D064030:S100 Calcium Binding Protein G; D014157:Transcription Factors; C433629:homeobox protein PITX3; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine