Dissecting Integrin-Dependent Regulation of Neural Stem Cell Proliferation in the Adult Brain

Controlling neural stem and progenitor cell (NSPC) proliferation is critical to maintain neurogenesis in the mammalian brain throughout life. However, it remains poorly understood how niche-derived cues such as β1-integrin-mediated signaling are translated into NSPC-intrinsic molecular changes to regulate NSPC activity. Here we show that genetic deletion of integrin-linked kinase (ILK) increases NSPC proliferation through PINCH1/2-dependent enhancement of c-Jun N-terminal protein kinase activity in both neurogenic regions of the adult mouse brain. This effect downstream of ILK signaling is mediated through loss of Ras suppressor unit-1 (RSU-1), as virus-based reconstitution of RSU-1 expression rescued the ILK-dependent effects on NSPC proliferation. Thus, we here identified an intracellular signaling cascade linking extrinsic integrin-mediated signaling to NSPC proliferation and characterized a novel mechanism that regulates NSPC activity in the adult mammalian brain.</jats:p

Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage

Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immune-competent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood–brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protectio