Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons

J Neurosci. 2011 Sep 7;31(36):12802-15. doi: 10.1523/JNEUROSCI.0898-11.2011.

Abstract

Pitx3 is a critical homeodomain transcription factor for the proper development and survival of mesodiencephalic dopaminergic (mdDA) neurons in mammals. Several variants of this gene have been associated with human Parkinson's disease (PD), and lack of Pitx3 in mice causes the preferential loss of substantia nigra pars compacta (SNc) mdDA neurons that are most affected in PD. It is currently unclear how Pitx3 activity promotes the survival of SNc mdDA neurons and which factors act upstream and downstream of Pitx3 in this context. Here we show that a transient expression of glial cell line-derived neurotrophic factor (GDNF) in the murine ventral midbrain (VM) induces transcription of Pitx3 via NF-κB-mediated signaling, and that Pitx3 is in turn required for activating the expression of brain-derived neurotrophic factor (BDNF) in a rostrolateral (SNc) mdDA neuron subpopulation during embryogenesis. The loss of BDNF expression correlates with the increased apoptotic cell death of this mdDA neuronal subpopulation in Pitx3(-/-) mice, whereas treatment of VM cell cultures with BDNF augments the survival of the Pitx3(-/-) mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell death in the absence of Pitx3. As the feedforward regulation of GDNF, Pitx3, and BDNF expression also persists in the adult rodent brain, our data suggest that the disruption of the regulatory interaction between these three factors contributes to the loss of mdDA neurons in Pitx3(-/-) mutant mice and perhaps also in human PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Cell Count
  • Corpus Striatum / cytology
  • Corpus Striatum / embryology
  • Corpus Striatum / metabolism*
  • Dopamine / physiology*
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology*
  • Homeodomain Proteins / physiology*
  • Hydroxydopamines / toxicity
  • Immunohistochemistry
  • In Situ Hybridization
  • Luciferases / metabolism
  • Mesencephalon / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / physiology
  • NF-kappa B / metabolism
  • Nerve Growth Factors / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Substantia Nigra / cytology
  • Substantia Nigra / embryology
  • Substantia Nigra / metabolism*
  • Sympatholytics / toxicity
  • Transcription Factors / physiology*

Substances

  • Brain-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor
  • Homeodomain Proteins
  • Hydroxydopamines
  • NF-kappa B
  • Nerve Growth Factors
  • Sympatholytics
  • Transcription Factors
  • homeobox protein PITX3
  • Luciferases
  • Dopamine