Control of cell fate by progenitor mitosis length and microcephaly-linked genes during cortical development

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Abstract   Microcephaly is a prevalent developmental cognitive disorder, with no available treatment. At least 12 genes underlie cases of primary recessive microcephaly in humans, and new efforts are needed to understand the function of these genes in the context of cortical development. During cortical development in the mouse, Radial Glia stem cells self-renew and produce both neurons and intermediate progenitors between Embryonic Days E11.5 and E18.5 to build the cortex. Microcephaly-linked genes have functions in cell cycle control, and are associated with centrosomes/microtubule spindle fibers. Our lab has recently discovered that prolonged mitosis in Radial Glia can alter cell fate, cause apoptosis, and potentiate microcephaly in mice, suggesting a plausible mechanism for altered cortical development in microcephaly. The goal of the research in this proposal is to further characterize how stem cell differentiation is affected by prolonged mitosis and to understand if microcephaly gene models in mice alter cortical stem cell mitosis duration and cell fate. Through pharmacologic delay of mitosis in Radial Glia in Specific Aim 1 and functional analysis of microcephaly genes Lis1, and Cdk5rap2 in Specific Aim 2, I will test the hypothesis that Radial Glia fate choice is influenced by mitosis duration across development, and that microcephaly-linked genes can control cell fate decisions by modulating Radial Glia mitosis. Preliminary data indicate prolonged mitosis can change the type of neuron produced by Radial Glia division, altering the normal progression of excitatory neuron type generation. Additionally, overexpression of Lis1, a microcephaly gene, alters length of mitosis in Radial Glia as well as alters the proportion of neurogenic versus proliferative divisions. It is not well understood how microcephaly-linked genes underlie the human disorder, but these preliminary results suggest altered cell fates due to prolonged mitosis can explain abnormal cortical development in microcephaly. Upon completion of the proposed aims, we will have critical insight into the function of microcephaly genes which will enable future studies toward effective treatment. Additionally we will further understand the role of mitosis duration during cortical development.