The role of Bcl-2 proteins in cell fate determination during neurogenesis.

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Neurogenesis is key to development of the nervous system. It is the process of how neural progenitor cells produce neurons that form the brain. For neurons to be formed, neural progenitor cells must switch from dividing to produce more progenitor cells (proliferating cells) to dividing to produce non-proliferating cells that become neurons (differentiating cells). Neurogenesis involves a complex interaction between different cell signaling pathways including the cell cycle machinery, metabolism and differentiation. How these pathways interact and what structures within cells regulate their timely coordination is under active investigation. Research is focusing on the role of mitochondria, organelles within cells that generate energy for the cell to function. During neurogenesis, changes in mitochondrial shape and size are observed. Changes in mitochondrial size and shape are regulated by opposing processes: fission and fusion. Mitochondrial fission results in mitochondria constricting and dividing into 2 smaller mitochondria while fusion joins two or more mitochondria. Recently differences in fission and fusion levels in neural progenitor cells were shown to determine whether a progenitor cell becomes a neuron or remains a progenitor cell. Mechanisms of mitochondrial fission and fusion are understood; however, the upstream signals that regulate fission and fusion and determine whether a cell becomes a neuron or progenitor cell (cell fate) is not known.       My research program focusses on identifying the roles of a family of proteins that regulate survival of neural progenitor cells during neurogenesis. This protein family has been shown to have diverse functions in the cell besides regulating cell survival. We are examining family member Mcl-1, which is expressed on mitochondria. To understand Mcl-1's role on mitochondria, we generated mice in which the Mcl-1 gene is not expressed (knocked out) (Mcl-1 knockout = MKO). Our research shows that during neurogenesis, MKO neural progenitor cells have two-fold more mitochondria than neural progenitors from littermate control mice. Increased numbers of mitochondria in MKO neural progenitor cells suggests higher rates of mitochondrial fission. We next examined whether increased levels of mitochondrial fission in MKO neural progenitors had an impact on cell fate determination (proliferative divisions vs differentiative divisions) during neurogenesis. Our results showed more neurons formed (differentiative divisions) in MKO brains compared to control brains. These findings suggest that Mcl-1 inhibits mitochondrial fission to regulate cell fate during neurogenesis. This research project is to identify the mechanism how this works.