Integrins and their interactions with extracellular matrix proteins (ECM) regulate many cellular processes but their role in neural stem cell biology is poorly defined. Here we focus on a novel integrin-ECM interaction that defines a permissive environment for stem cell self-renewal and neurogenesis in the adult brain. Neural stem cells persist in the adult mammalian brain and support the continuing production of neurons and glia. Although glia are produced in all areas of the brain, native neurogenesis is restricted to the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Neurogenesis can be triggered in other areas of the brain, for example by injury, but the production and retention of new neurons is inefficient and abortive at best. A better understanding of local environments that naturally support the maintenance of a stem cell pool as well as their efficient use in neurogenesis could lead to significant advances in neural repair/regeneration. Toward this end, we have identified several integrin-ECM interactions that are selectively localized to the native neurogenic areas of the brain. In vitro, we show that these interactions gate neural stem and progenitor cell response to mitogens and here we propose studies to define the specific mechanisms used within the adult neurogenic niche to: 1) maintain and regulate stem cell self-renewal and stem cell pool size;2) regulate the transient amplification and survival of newly generated neuroblasts;and 3), mediate physiological signaling that controls hippocampal neurogenesis in response to physical exercise or learning experiences.
Neural repair and regeneration in the brain is one of the most difficult yet potentially rewarding goals in stem cell research. In this application we take advantage of an area of the brain that naturally produces new neurons to more precisely define the microenvironment that maintains stem cells and regenerative activity throughout life. This unique neurogenic niche utilizes a complex interaction of cells and signals to maintain and regulate neurogenesis and we have recently found that extracellular matrix proteins are integral and essential in this cellular and biochemical environment. Here we propose to 1) further refine our understanding of the molecular interactions that promote or inhibit the stem cells in the generation, survival and integration of new neurons;2) evaluate the intracellular signaling cascades that underlie the phenomenon behind the generation of new neurons;3) develop and demonstrate the role of these cellular and molecular components in regulating adult neurogenesis in transgenic animal models. We anticipate that the outcome of the proposed studies will significantly advance our understanding of natural regenerative processes and provide insights into improving the efficacy of future stem cell therapies for a variety of neurological injuries and diseases.
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| Haditsch, Ursula; Anderson, Matthew P; Freewoman, Julia et al. (2013) Neuronal Rac1 is required for learning-evoked neurogenesis. J Neurosci 33:12229-41 |
