Molecular control of self-renewal and neurogenic characteristics of cortical progenitors

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The cerebral cortex plays a key role in many higher order functions in humans and therefore malformation or damage to the cortex greatly affects our well-being. The cortex is a tissue with very few adult stem cells and therefore has limited capacity to generate new neurons. Decoding the mechanisms that control the self-renewing potential of the cortical progenitors would shed light on the causes of neurodevelopmental disorders, and may also help to develop strategies to repair the damaged and/or aged cortex. My aim in this proposal is to investigate fate-switching mechanisms that change self-renewing progenitors into those capable of generating neurons in the cerebral cortex. Early cortical progenitors are self-renewing and expand the population of progenitors. Subsequently they differentiate into neural progenitors, which undergo a limited number of cell divisions generating neurons. In other words cortical progenitors undergo fundamental changes in their characteristics during early corticogenesis: from self-renewing progenitors to neurogenic progenitors with limited self-renewing capacity but that competently generate neurons. But how the self-renewing and neurogenic progenitor fates are determined and how the transition processes regulated remains an important but unsolved question. Previously I have found that Fgf10, one of the fibroblast growth modulates differentiation of self-renewing to neurogenic progenitors. Based in my initial finding, I aim to identify novel factors determining the fate of self-renewing, neurogenic progenitors and its transition. Determining the underlying mechanisms that control the decision of the neural progenitors to renew or differentiate is very important for at least two reasons. Firstly, balancing self-renewing proliferation and differentiation of neural progenitors is a crucial developmental mechanism to ensure proper growth of the nervous systems. Impairment of progenitor self-renewal results in immature and reduced brain growth, whilst uncontrolled over-proliferation often causes oversized brains and/or cancers. Secondly, the use of stem/progenitor cells offers enormous potential to develop novel strategies to repair damaged nervous systems with little natural regenerative capacity. I firmly believe that the study proposed here will provide new findings to explain fundamental characteristics of cortical progenitors: self-renewing or competent for neurogenesis. This study will provide insights into the genetic program of cortical progenitors that determines their self-renewal potential and neurogenic competency. As the adult cortex has little potential for neurogenesis due of the lack of neural progenitors, developing a regenerative medicine approach is crucial for repair of the cortex injured by various mechanical damages, ischemia, or neurodegenerative diseases. Identifying and characterizing key factors of cortical progenitor differentiation as proposed here will not only shed light on the fundamental mechanisms of neural progenitor differentiation, but may provide us with genetic tools or help to discover drugs that enable direct reprogramming of in vivo differentiated cells (which can no longer regenerate neurons) into neurogenic or self-renewing progenitors. In a following project, I will test the possibility of whether my candidate genes could be utilized to reprogram differentiated cells into self renewal and/or neurogenic states that may provide newly generating neurons in the adult cortex.