ApoER2 and VLDLr Are Required for Mediating Reelin Signalling Pathway for Normal Migration and Positioning of Mesencephalic Dopaminergic Neurons

Ahmed Sharaf,Hans H Bock,Kerstin Krieglstein,Björn Spittau,Elisabeth Bouché,Ramin Homayouni

doi:10.1371/journal.pone.0071091

Abstract

The migration of mesencephalic dopaminergic (mDA) neurons from the subventricular zone to their final positions in the substantia nigra compacta (SNc), ventral tegmental area (VTA), and retrorubral field (RRF) is controlled by signalling from neurotrophic factors, cell adhesion molecules (CAMs) and extracellular matrix molecules (ECM). Reelin and the cytoplasmic adaptor protein Disabled-1 (Dab1) have been shown to play important roles in the migration and positioning of mDA neurons. Mice lacking Reelin and Dab1 both display phenotypes characterised by the failure of nigral mDA neurons to migrate properly. ApoER2 and VLDLr are receptors for Reelin signalling and are therefore part of the same signal transduction pathway as Dab1. Here we describe the roles of ApoER2 and VLDLr in the proper migration and positioning of mDA neurons in mice. Our results demonstrate that VLDLr- and ApoER2-mutant mice have both a reduction in and abnormal positioning of mDA neurons. This phenotype was more pronounced in VLDLr-mutant mice. Moreover, we provide evidence that ApoER2/VLDLr double-knockout mice show a phenotype comparable with the phenotypes observed for Reelin- and Dab1- mutant mice. Taken together, our results demonstrate that the Reelin receptors ApoER2 and VLDLr play essential roles in Reelin-mediated migration and positioning of mDA neurons.

Highlights

Parkinson’s disease (PD) is an age-associated neurodegenerative disorder characterized by the gradual degeneration and loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) of the midbrain, which presents in the clinic as movement and behavioural disorders due to the reduction of dopamine levels in the striatum
We found a significant reduction in the total numbers of nigral dopaminergic neurons in ApoER22/2 (Fig. 1c, d) and VLDLR2/2 mice (Fig. 1g, h) when compared to the corresponding wildtype littermates (Fig. 1a, b, e, f).The reduction of dopaminergic neurons in substantia nigra compacta (SNc) was only apparent and significant in the intermediate sections of the midbrain
There was an increase in the mean total number of TH-positive dopaminergic neurons in the ventral tegmental area (VTA) of VLDLr-mutant mice when compared to wildtype mice (Fig. 1k), the total estimated number of mesencephalic dopaminergic (mDA) neurons was not significantly different (Fig. 1l), suggesting that the disorganization and abnormal positioning of midbrain dopaminergic neurons in the absence of ApoER2 or VLDLr might be related to a failure of the nigral neurons to reach their proper location in the lateral mesencephalon

Summary

Introduction

Parkinson’s disease (PD) is an age-associated neurodegenerative disorder characterized by the gradual degeneration and loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) of the midbrain, which presents in the clinic as movement and behavioural disorders due to the reduction of dopamine levels in the striatum. Dopaminergic progenitor cells are generated in the mouse isthmic organizer located in the ventricular zone between E10 and E12 and migrate first ventrally along radial glial cells toward the pial surface of the midbrain and laterally along tangential nerve fibers originating from the lateral part of the mesencephalon [2] to reach their final destinations. There they form three different neuronal populations, the substantia nigra pars compacta (SNc, A9), ventral tegmental area (VTA, A10) and retrorubral field (RRF) [3], [4], [5], [2] and [6]).

Methods

Results

Conclusion