Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aphakia / genetics
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Aphakia / pathology
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Aphakia / physiopathology
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Apoptosis
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Cell Survival
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Dopamine / deficiency
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Dopamine / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Humans
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Male
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Mesencephalon / cytology*
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Mesencephalon / embryology
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Mesencephalon / growth & development
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Mesencephalon / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Motor Activity / genetics
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Motor Activity / physiology*
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Nerve Degeneration / genetics
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Nerve Degeneration / metabolism
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Neurons / cytology
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Neurons / metabolism
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Parkinson Disease / genetics
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Parkinson Disease / pathology
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Parkinson Disease / physiopathology
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Homeodomain Proteins
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Transcription Factors
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homeobox protein PITX3
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Tyrosine 3-Monooxygenase
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Dopamine