Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system

• Published in: PLoS biology Vol. 5; no. 3; p. e39
• Main Authors: Kramer, Edgar R, Aron, Liviu, Ramakers, Geert M J, Seitz, Sabine, Zhuang, Xiaoxi, Beyer, Klaus, Smidt, Marten P, Klein, Rüdiger
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-03-2007; Public Library of Science (PLoS)
• Subjects: Animals; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Corpus Striatum - metabolism; Corpus Striatum - pathology; Genetic aspects; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Health aspects; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegeneration; Neurons; Neurotrophic functions; Parkinson's disease; Physiological aspects; Proteins; Proto-Oncogene Proteins c-ret - metabolism; Receptor, trkB - genetics; Signal Transduction; Substantia Nigra - metabolism; Substantia Nigra - pathology; Immunohistochemistry; Receptor, trkB; Signal Transduction; Substantia Nigra; Mice, Inbred C57BL; Mice, Transgenic; Animals; Glial Cell Line-Derived Neurotrophic Factor Receptors; Glial Cell Line-Derived Neurotrophic Factor; Corpus Striatum; Brain-Derived Neurotrophic Factor; Proto-Oncogene Proteins c-ret; Mice
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0050039

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.