Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system.
Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.
Kramer
Edgar R
ER
Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, Martinsried, Germany. ekramer@neuro.mpg.de
Aron
Liviu
L
Ramakers
Geert M J
GM
Seitz
Sabine
S
Zhuang
Xiaoxi
X
Beyer
Klaus
K
Smidt
Marten P
MP
Klein
Rüdiger
R
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*
D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051096:Proto-Oncogene Proteins c-ret; D020813:Receptor, trkB; C494999:Ret protein, mouse