Stem cells reside in specialized niches that regulate their self-renewal and differentiation. The vasculature is emerging as an important component of stem cell niches. Here, we show that the adult subventricular zone (SVZ) neural stem cell niche contains an extensive planar vascular plexus that has specialized properties. Dividing stem cells and their transit-amplifying progeny are tightly apposed to SVZ blood vessels both during homeostasis and regeneration. They frequently contact the vasculature at sites that lack astrocyte endfeet and pericyte coverage, a modification of the blood-brain barrier unique to the SVZ. Moreover, regeneration often occurs at these sites. Finally, we find that circulating small molecules in the blood enter the SVZ. Thus, the vasculature is a key component of the adult SVZ neural stem cell niche, with SVZ stem cells and transit-amplifying cells uniquely poised to receive spatial cues and regulatory signals from diverse elements of the vascular system.
Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.
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