The function of the brain requires that the proper number of cells be produced and that diverse cell populations are present in the correct locations. While some flexibility exists in maturity, the programs that guide the generation and maturation of neurons act primarily during embryonic development. Indeed, during brain development, diverse sets of molecules participate in choreographing the formation of brain structures. Transcription factors, proteins that activate or repress sets of target genes, play a central role in specifying neuronal characteristics. One category of transcription factors, Sox genes, and particularly the SoxC subset that includes Sox 4 and Sox 11, have been studied in neural systems and proposed to promote neuronal differentiation. Our studies of Sox4 and 11 in the cerebral cortex, the most complex and integrative part of the mammalian brain, have revealed hitherto unknown complexities in the roles of these transcription factors in coordinating brain development. Specifically, we hypothesize that Sox4 initially acts in directing a critical intermediate progenitor cell state and then, in parallel with Sox11, promotes the differentiation o neurons at a later time points. Using molecular, cellular, and biochemical approaches as well as stable and transient manipulation of Sox4 and Sox11 function in cell culture and in the forming cortex of mice, it is the goal of this proposal to understand how Sox4 and Sox 11 carry out these functions and participate in the coordination of cell fates in cerebral cortical development. College students will be participating in all of our experiments, thus enhancing the scientific research community in the College of Arts and Sciences at Georgetown University.
Since the vast majority of neurons in the brain are produced during embryonic life, understanding the molecular cascades that promote cell division and neuronal differentiation is critical for generating appropriately complex circuitry. We propose two major roles for SoxC transcriptional regulators in corticogenesis: Sox11 promotes neuronal maturation, while Sox4 acts first to promote a unique proliferative state, called an intermediate progenitor cell, before transitioning a cell into a differentiated neuron. Through this R15 proposal, we intend to strengthen Georgetown University's College of Arts and Science's research environment while welcoming undergraduates into a sophisticated and impactful developmental neuroscience research endeavor.
