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Title: Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals

Author
item KAZANIS, ILIAS - University Of Cambridge
item LATHIA, JUSTIN - University Of Cambridge
item VADAKKAN, TEGY - Baylor College Of Medicine
item RABORN, ERIC - Baylor College Of Medicine
item WAN, RUIQIAN - National Institute On Aging (NIA, NIH)
item MUGHAL, MOHAMED - National Institute On Aging (NIA, NIH)
item ECKLEY, D - National Institute On Aging (NIA, NIH)
item SASAKI, TAKAKO - Oregon Health & Science University
item PATTON, BRUCE - Oregon Health & Science University
item MATTSON, MARK - National Institute On Aging (NIA, NIH)
item HIRSCHI, KAREN - Children'S Nutrition Research Center (CNRC)
item DICKINSON, MARY - Baylor College Of Medicine
item FFRENCH-CONSTANT, CHARLES - University Of Cambridge

Submitted to: Journal of Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/6/2010
Publication Date: 7/21/2010
Citation: Kazanis, I., Lathia, J.D., Vadakkan, T.J., Raborn, E., Wan, R., Mughal, M.R., Eckley, D.M., Sasaki, T., Patton, B., Mattson, M.P., Hirschi, K.K., Dickinson, M.E., Ffrench-Constant, C. 2010. Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals. Journal of Neuroscience. 30(29):9771-9781.

Interpretive Summary: There is a set of structures (called ventricles) in the inside of the brain which contain cerebrospinal fluid (a clear, colorless bodily fluid which is found in and around the brain and spinal cord). The largest of these ventricles run lengthwise through the middle of the brain and are called the lateral ventricles; the first cell layers which immediately surround the lateral ventricles are called the subependymal zone (from now on called the SEZ). This SEZ area has a high concentration of neural stem cells (from now on called NSCs), and it is these NSCs which continuously generate new brain cells (neurons). This specific area of the brain is very complex, and has a high concentration of blood vessels whereas other areas of the brain do not. This paper tries to describe the way scaffolding molecules that a cell attaches to (from now on called ECM) and their receptors might regulate this differential behavior. This paper shows that NSCs and precursors proceed through cell division in the same areas within the SEZ of adult male mice and that distance from the ventricle (compared to distance from blood vessels) is a stronger limiting factor when neurons are being generated. Furthermore, the paper shows that NSCs and precursors are embedded in ECM that has a high concentration of laminin (an important protein in one of the layers of the basement membrane which lines cavities and surfaces of organs, or the interior surface of blood vessels), and that they also express different levels of ECM receptors. Finally, this paper shows that when NSCs are activated so that they replenish their surroundings after it has been depleted of precursors, expression of laminin receptors is increased. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated by the exposure to varying degrees of extracellular signals, but rather through an (internal) intrinsic regulation of their interaction with their immediate surroundings.

Technical Abstract: The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice--albeit with NSCs nearer ependymal cells--and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of alpha6beta1 integrin, syndecan-1, and lutheran, and in vivo blocking of beta1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.