Molecular mechanisms of neural stem cells migration, survival and differentiation

Abstract

Neurogenesis, or generation of new neurons, occurs in specific regions of the adult mammalian brain, in specialized niches that maintain cells with stem cell characteristics. Until now two neurogenic niches have been identified in the adult mammalian central nervous system, the hyppocampal subgranular zone and the subventricular zone, composed by cells adjacent to the ependimal cells lining the lateral ventricules. In physiological conditions, neural stem cells present in the neurogenic niches generate neuronal precursors, known as neuroblasts, which migrate from the niches to their final destination, where they are incorporated into the existing circuitry. Neural stem cells originated in the hyppocampal subgranular zone originate neuroprogenitors that will replace damaged cells in the hippocampus, whereas neuroblasts generated from neural stem cells in the subventricular zone migrate towards the olfactory bulb using the rostral migratory stream, where they differentiate in neurons, as has been already described in rodents. In pathological situations, such as in cranioencephalic trauma, cerebral ischemia or neurodegenerative disorders, neuronal death induces the production of signals that will stimulate neural stem cell proliferation increasing the generation of neuroblasts, which will migrate towards the regions where there was neuronal loss. The molecular and cellular mechanisms involved in proliferation, pluripotency maintenance, migration, differentiation, and neuronal integration are partially known at the moment, but there are still questions to be answered. Knowing the cellular and molecular mechanisms involved in neural stem cell response to physiological and pathological stimuli will be fundamental to the understanding and, eventually, proposal of new therapeutic interventions to treat damage to the central nervous system. In this project we intend to study part of this complex process by evaluating three aspects of the reposition of neuronal loss: migration, survival and differentiation of neuroblasts. Our experimental approach will involve in vitro studies using neural stem cells from the subventricular zone of adult mice as well as in vivo studies using animal models for cranioencephalic trauma and Parkinson´s disease in mice. (AU)