Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System

Edgar R Kramer,Xiaoxi Zhuang,Marten P Smidt,Liviu Aron,Rüdiger Klein,Klaus Beyer,Geert M J Ramakers,Sabine Seitz,Richard G M Morris

doi:10.1371/journal.pbio.0050039

Abstract

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.

Highlights

The ventral mesencephalon contains the majority of dopaminergic (DA) neurons in the vertebrate brain with important functions for maintaining the mental and physical health of the organism
Glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) have been suggested as survival factors for midbrain dopaminergic neurons, a group of neurons primarily affected in Parkinson disease
For Dopamine transporter (DAT)-Cre mice, it was previously shown that virtually all (95%) of tyrosine hydroxylase (TH)-positive cells in substantia nigra pars compacta (SNpc) and the nearby ventral tegmental area (VTA) regions express Cre and show Cre-mediated recombination in adult mice, whereas weak lacZ reporter activity was seen in DA neurons of the olfactory bulb and hypothalamus

Summary

Introduction

The ventral mesencephalon contains the majority of dopaminergic (DA) neurons in the vertebrate brain with important functions for maintaining the mental and physical health of the organism They form two prominent pathways: DA neurons of the substantia nigra pars compacta (SNpc) extend their axons mainly into the dorsal striatum (caudateputamen) to form the nigrostriatal pathway essential for the control of voluntary motor behavior. DA neurons of the ventral tegmental area (VTA) project their fibers mostly into the ventral striatum (nucleus accumbens), olfactory tubercle, septum, amygdala, hippocampus, and cortex collectively referred to as the mesocorticolimbic system. This system has important function in controlling emotion-based behavior such as motivation and reward. The questions about the molecular etiology of PD and the selective neuronal vulnerability have not been answered satisfactorily

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