Differential activation of microglia in neurogenic versus non‐neurogenic regions of the forebrain

The adult brain subventricular zone (SVZ) produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) in a specialized niche. Galectin-3 (Gal-3) regulates proliferation and migration in cancer and is expressed by activated macrophages after brain injury. The function of Gal-3 in the normal brain is unknown, but we serendipitously found that it was expressed by ependymal cells and SVZ astrocytes in uninjured mice. Ependymal cilia establish chemotactic gradients and astrocytes form glial tubes, which combine to aid neuroblast migration. Whole-mount preparations and electron microscopy revealed that both ependymal cilia and SVZ astrocytes were disrupted in Gal3−/− mice. Interestingly, far fewer new BrdU+ neurons were found in the OB of Gal3−/− mice, than in wild-type mice 2 weeks after labeling. However, SVZ proliferation and cell death, as well as OB differentiation rates were unaltered. This suggested that decreased migration in vivo was sufficient to decrease the number of new OB neurons. Two-photon time-lapse microscopy in forebrain slices confirmed decreased migration; cells were slower and more exploratory in Gal3−/− mice. Gal-3 blocking antibodies decreased migration and dissociated neuroblast cell–cell contacts, whereas recombinant Gal-3 increased migration from explants. Finally, we showed that expression of phosphorylated epidermal growth factor receptor (EGFR) was increased in Gal3−/− mice. These results suggest that Gal-3 is important in SVZ neuroblast migration, possibly through an EGFR-based mechanism, and reveals a role for this lectin in the uninjured brain.

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“…+ SVZ microglial cells are constitutively semi-activated (Goings et al, 2006), most CD45 + cells in the SVZ did not express Gal-3 ( Fig. 1L-N).…”

Section: Gal-3 Is Expressed By a Subset Of Svz Cellsmentioning

confidence: 95%

Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb

Comte

Kim

Young

et al. 2011

Journal of Cell Science

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“…Regional heterogeneity and populational segregation of microglia in tissues and preparations were demonstrated by morphology, selective detection of constitutive or inducible mRNAs and proteins [e.g., for TNF-␣, IL-6, IGF-I, integrins, CD4, CD11c, CD34, CD40, CD45, CD86, major histocompatibility complex (MHC) class II, Fc␥RII, iNOS, and members of the neurotrophin family], or differences in the proliferative potential (6,111,128,192,247,287,327,351,438,475,485,487,488,552,755,809,810,825,854,872,993). Heterogeneity was also observed in microglia from the aging brain where surprising differences between individuals were found (579,834).…”

Section: Microglia: From the Warden (Survelliance) To Cleaner (Mamentioning

confidence: 99%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,006

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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“…Possibly, activated microglia in the SVZ/striatum secrete other factors than those present in the dentate gyrus. Indeed, microglia in the SVZ show a greater response to injury, in terms of activation and proliferation, compared to microglia in non-neurogenic regions (Goings et al, 2006).…”

Section: Lesion-induced Microglial Activation Promotes Nspc Proliferamentioning

confidence: 99%

Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes

et al. 2010

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Here, we developed an ex vivo method to investigate how the proliferation of NSPCs changes over time after experimental stroke or excitotoxic striatal lesion in the adult rat brain by studying the effects of microglial cells derived from an injured brain on NSPCs. We isolated NSPCs from the SVZ of brains with lesions and analyzed their growth and differentiation when cultured as neurospheres. We found that NSPCs isolated from the brains 1-2 weeks following injury consistently generated more and larger neurospheres than those harvested from naïve brains. We attributed these effects to the presence of microglial cells in NSPC cultures that originated from injured brains. We suggest that the effects are due to released factors because we observed increased proliferation of NSPCs isolated from non-injured brains when they were exposed to conditioned medium from cultures containing microglial cells derived from injured brains. Furthermore, we found that NSPCs derived from injured brains were more likely to differentiate into neurons and oligodendrocytes than astrocytes. Our ex vivo system reliably mimics what is observed in vivo following brain injury. It constitutes a powerful tool that could be used to identify factors that promote NSPC proliferation and differentiation in response to injury-induced activation of microglial cells, by using tools such as proteomics and gene array technology.4

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Differential activation of microglia in neurogenic versus non‐neurogenic regions of the forebrain

Cited by 91 publications

References 72 publications

Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb

Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb

Physiology of Microglia

Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes

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