The brain is generated by the regulated production of neurons and glial cells from pools of neural stem cells. Defects in neural stem cell function may be responsible for some congenital brain malformations, neurological abnormalities and psychological disorders in humans. Importantly, stem cells remain in some regions of the adult mammalian brain but fail to regenerate new brain tissue after injury or during disease. We aim to understand the molecular mechanisms that control the regulation of neural stem cells and how these signals may be influenced by disease and aging. Over the past few years, we have identified a striking diversity in the neural stem cell pools within the adult mammalian brain. Using genetic analyses we are now able to identify, trace and isolate these different neural stem cell populations and to study their transition between active and quiescent states. We have identified a novel mechanism of neural stem cell regulation whereby the expression of key regulatory proteins is directly controlled by mRNA destabilization in addition to gene transcription. We plan experiments to study in more detail the molecular machinery that controls the process of neural stem cell differentiation beyond the level of the gene. We will identify targets of this molecular pathway through state-of-the-art molecular genetics. In addition, we will study the signaling mechanisms that control differences in stem cell activity during aging and disease. A deeper understanding of the regulatory mechanisms that control the activity of neural stem cells in the developing and adult brain and their differentiation potential could have wide reaching implications for human therapy and potentially brain regeneration.