Reelin Controls Progenitor Cell Migration in the Healthy and Pathological Adult Mouse Brain

Sandrine Courtès,Harold Cremer,Lluís Pujadas,Eduardo Soriano,Julien Vernerey,Pascale Durbec,Karine Magalon,Myriam Cayre,Domingos Henrique

doi:10.1371/journal.pone.0020430

Abstract

Understanding the signals that control migration of neural progenitor cells in the adult brain may provide new therapeutic opportunities. Reelin is best known for its role in regulating cell migration during brain development, but we now demonstrate a novel function for reelin in the injured adult brain. First, we show that Reelin is upregulated around lesions. Second, experimentally increasing Reelin expression levels in healthy mouse brain leads to a change in the migratory behavior of subventricular zone-derived progenitors, triggering them to leave the rostral migratory stream (RMS) to which they are normally restricted during their migration to the olfactory bulb. Third, we reveal that Reelin increases endogenous progenitor cell dispersal in periventricular structures independently of any chemoattraction but via cell detachment and chemokinetic action, and thereby potentiates spontaneous cell recruitment to demyelination lesions in the corpus callosum. Conversely, animals lacking Reelin signaling exhibit reduced endogenous progenitor recruitment at the lesion site. Altogether, these results demonstrate that beyond its known role during brain development, Reelin is a key player in post-lesional cell migration in the adult brain. Finally our findings provide proof of concept that allowing progenitors to escape from the RMS is a potential therapeutic approach to promote myelin repair.

Highlights

Cell migration is a critical aspect of brain development as it is required for correct positioning of specific cell populations
Reelin is endogenously up-regulated after brain lesion We first questioned whether endogenous Reelin expression could be modulated in response to brain injury
In conclusion, our study reveals a new role for Reelin in the healthy and in the injured adult brain and provides the proof of concept that targeting endogenous subventricular zone (SVZ)/rostral migratory stream (RMS) cell migration is a valuable strategy to promote regenerative processes

Summary

Introduction

Cell migration is a critical aspect of brain development as it is required for correct positioning of specific cell populations. Cell migration in the adult brain is quite limited. One notable exception is the rostral migratory stream (RMS). In rodents, this pathway constitutes the highway for subventricular zone (SVZ)-derived neural progenitors en route to the olfactory bulb (OB). Tangential homophilic chain migration is a hallmark of cell migration in the RMS [1]. Often following blood vessels [2], are surrounded by a tunnel of astrocytes [2,3], which facilitate progenitor cell migration in an adult environment and contribute to restricting them to the RMS

Results

Discussion

Conclusion