Abstract
Slit1 is a secreted axon guidance molecule, also involved in adult neurogenesis. In physiological conditions, Slit1 loss promotes ectopic dispersal of SVZ-derived neural precursors (SVZ-NPCs) into periventricular structures such as the corpus callosum. Demyelination of the corpus callosum triggers SVZ-NPC migration to ectopic locations and their recruitment by the lesion, suggesting a possible role for Slit1 in SVZ-NPCs ectopic dispersal regulation in pathological conditions. Here, we have investigated the function of Slit1 protein in the recruitment of SVZ-NPCs after CNS demyelination. We find that the dynamics of oligodendrogenesis and temporal profile of developmental myelination in Slit1–/– mice are similar to Slit1+/− controls. SVZ micro-dissection and RT-PCR from wild-type mice, show that Slits and Robos are physiologically regulated at the transcriptional level in response to corpus callosum demyelination suggesting their role in the process of SVZ-NPC ectopic migration in demyelinating conditions. Moreover, we find that the number of SVZ-NPCs recruited by the lesion increases in Sli1–/– mice compared to Slit1+/− mice, leading to higher numbers of Olig2+ cells within the lesion. Time-lapse video-microscopy of immuno-purified NPCs shows that Slit1-deficient cells migrate faster and make more frequent directional changes than control NPCs, supporting a cell-autonomous mechanism of action of Slit1 in NPC migration. In conclusion, while Slit1 does not affect the normal developmental process of oligodendrogenesis and myelination, it regulates adult SVZ-NPC ectopic migration in response to demyelination, and consequently oligodendrocyte renewal within the lesion.
Highlights
The discovery of on-going neurogenesis throughout life in the majority of mammals (Hinds, 1968; Altman, 1969) as well as the identification of neural stem/precursor cells (NPCs) in the adult rodent (Reynolds and Weiss, 1992), non-human primate (Kornack and Rakic, 2001; Pencea et al, 2001) and human CNS (Kirschenbaum et al, 1994) opens new perspectives for self-repair of brain damage
We assessed the expression of the myelin basic protein (MBP), a major constituent of myelin (Norton and Cammer, 1984), at
Because subventricular zone (SVZ)-derived cells can be recruited by the LPC-induced focal demyelination and differentiate into cells of the oligodendrocyte lineage, we investigated the impact of Slit1 deficiency on these events
Summary
The discovery of on-going neurogenesis throughout life in the majority of mammals (Hinds, 1968; Altman, 1969) as well as the identification of neural stem/precursor cells (NPCs) in the adult rodent (Reynolds and Weiss, 1992), non-human primate (Kornack and Rakic, 2001; Pencea et al, 2001) and human CNS (Kirschenbaum et al, 1994) opens new perspectives for self-repair of brain damage (reviewed in Picard-Riera et al, 2004; Nait-Oumesmar et al, 2008; Okano and Sawamoto, 2008; Kaneko and Sawamoto, 2009; Spigoni et al, 2014). The SVZ-NPCs, self-expand in response to epidermal growth factor (EGF) and fibroblast growth factor (FGF), and differentiate into neurons, astrocytes and oligodendrocytes upon growth factor retrieval (Reynolds and Weiss, 1992; Lois and Alvarez-Buylla, 1993) In vivo, they retain the capacity to divide and migrate in chain through the rostral migratory stream (RMS) to the olfactory bulb (OB) where they become peri-glomerular and granular neurons (Luskin, 1993; Lois and Alvarez-Buylla, 1994). While little is known about the molecular machinery regulating ectopic migration of the adult SVZ-NPCs, gaining insights into this process could promote their involvement in brain repair
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