Proliferative asymmetry in the neural stem cell lineage established by asymmetric cell division - ABSTRACT In the proposed work, I will be investigating how neural stem cells establish ‘proliferative asymmetries’, which are responsible for precisely controlling the development and repair of the central nervous system. During development and tissue repair, stem cells are triggered to proliferate. While proliferation is necessary, it must be precise to prevent overgrowth that can lead to tumorigenesis. As neural stem cells proliferate, they commonly divide asymmetrically. The ability to undergo asymmetric cell division is a highly conserved feature of neural stem cells across all animals. Asymmetric cell division produces one daughter cell that retains the neural stem cell identity, and one daughter cell which takes on a neuron-producing progenitor cell identity. A key difference between these two daughter cells is that the stem cell will rapidly reenter the cell cycle and divide again, while the progenitor cell will divide much more slowly or stop dividing all together. This proliferative asymmetry ensures that the proper number of neurons are produced, and its disruption leads to defects in neurogenesis. The molecular basis for this proliferative asymmetry mostly unknown. I will focus my independent research program around the mechanisms which establish this proliferative asymmetry. I hypothesize that this proliferative asymmetry is established by the differential inheritance of proliferation promoting factors during asymmetric cell division. I plan to learn how neural stem cells generate proliferative asymmetries in both invertebrates and vertebrates, through the use of Drosophila and zebrafish animal models. Studying both animal models will allow me to identify conserved and divergent modes of generating proliferative asymmetries in neural stem cells, while also providing me with new training opportunities. Both animal models are highly amenable to live cell imaging of neural stem cells in developing brains. In Aim 1, I will screening for proliferation regulators which are polarized in the mother neural stem cell. In Aim 2, I will determine how polarized proliferative regulators contribute to proliferative asymmetries between sibling cells. In Aim 3, I will determine how PAR polarity proteins regulate the PI3K proliferation pathway. Through my initial screening, I have already discovered one promising candidate that appears to mediate the proliferative asymmetry in the neural stem cell lineage, the lipid PIP3. PIP3 is transiently produced by the mother neural stem cell just before division, becomes polarized to one side of the cell, and gets inherited by the daughter cell which retains the neural stem cell identity. Discovering how PIP3 and other factors establish proliferative asymmetries during asymmetric cell division will advance our understanding of how neural stem cells mediate development and tissue repair. Through training activities aimed at improving my skills in grant writing, scientific teaching, and mentoring, I will be better prepared to run my own laboratory. The scientific discoveries and training this proposal will facilitate, will be foundational to building my independent research program.
