Leptin-dependent neurotoxicity via induction of apoptosis in adult rat neurogenic cells.

Adipocyte-derived hormone leptin has been recently implicated in the control of neuronal plasticity. To explore whether modulation of adult neurogenesis may contribute to leptin control of neuronal plasticity, we used the neurosphere assay of neural stem cells derived from the adult rat subventricular zone (SVZ). Endogenous expression of specific leptin receptor (ObRb) transcripts, as revealed by RT-PCR, is associated with activation of both ERK and STAT-3 pathways via phosphorylation of the critical ERK/STAT-3 amino acid residues upon addition of leptin to neurospheres. Furthermore, leptin triggered withdrawal of neural stem cells from the cell cycle as monitored by Ki67 labeling. This effect was blocked by pharmacological inhibition of ERK activation thus demonstrating that ERK mediates leptin effects on neural stem cell expansion. Leptin-dependent withdrawal of neural stem cells from the cell cycle was associated with increased apoptosis, as detected by TUNEL, which was preceded by cyclin D1 induction. Cyclin D1 was indeed extensively colocalized with TUNEL-positive, apoptotic nuclei. Cyclin-D1 silencing by specific shRNA prevented leptin-induced decrease of the cell number per neurosphere thus pointing to the causal relationship between leptin actions on apoptosis and cyclin D1 induction. Leptin target cells in SVZ neurospheres were identified by double TUNEL/phenotypic marker immunocytofluorescence as differentiating neurons mostly. The inhibition of neural stem cell expansion via ERK/cyclin D1-triggered apoptosis defines novel biological action of leptin which may be involved in adiposity-dependent neurotoxicity.

Netrin 1 contributes to vascular remodeling in the subventricular zone and promotes progenitor emigration after demyelination.

Neural stem cells are maintained in the adult brain, sustaining structural and functional plasticity and to some extent participating in brain repair. A thorough understanding of the mechanisms and factors involved in endogenous stem/progenitor cell mobilization is a major challenge in the promotion of spontaneous brain repair. The main neural stem cell niche in the adult brain is the subventricular zone (SVZ). Following demyelination insults, SVZ-derived progenitors act in concert with oligodendrocyte precursors to repopulate the lesion and replace lost oligodendrocytes. Here, we showed robust vascular reactivity within the SVZ after focal demyelination of the corpus callosum in adult mice, together with a remarkable physical association between these vessels and neural progenitors exiting from their niche. Endogenous progenitor cell recruitment towards the lesion was significantly reduced by inhibiting post-lesional angiogenesis in the SVZ using anti-VEGF blocking antibody injections, suggesting a facilitating role of blood vessels for progenitor cell migration towards the lesion. We identified netrin 1 (NTN1) as a key factor upregulated within the SVZ after demyelination and involved in local angiogenesis and progenitor cell migration. Blocking NTN1 expression using a neutralizing antibody inhibited both lesion-induced vascular reactivity and progenitor cell recruitment at the lesion site. We propose a model in which SVZ progenitors respond to a demyelination lesion by NTN1 secretion that both directly promotes cell emigration and contributes to local angiogenesis, which in turn indirectly facilitates progenitor cell emigration from the niche.

Reelin controls progenitor cell migration in the healthy and pathological adult mouse brain.

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.