In the developing cerebral cortex there is a stereotyped pattern of neuronal and glial cell birth. To achieve this, stem cells alter their output over time in response to both intrinsic and extrinsic factors. The composition of the progenitor cell pool therefore changes over time with diverse sets of precursors with restricted developmental potential coexisting at any single-time point. Few intrinsic factors have been identified that control the transition from a progenitor cell to a lineage-restricted cell and differentiated cell. The long-term goals of this research are to understand the molecular and cellular basis of progenitor cell specification in the cerebral cortex. We have identified a forebrain restricted transcription factor, tailless (tlx), that is required for the timing of neurogenesis and gliogenesis in the telencephalon. Adult animals exhibit depletion of neurons in upper cortical layers and an enhanced number of glia in addition to reduced cell number in limbic associated structures. As a consequence of these developmental alterations, animals exhibit behavioural abnormalities including severe aggression, stereotypy, reduced contextual and cued conditioning and abnormal maternal instincts. We hypothesize that the tlx gene is a critical intrinsic regulator of a cortical neuronal progenitor cells decision to proliferate or differentiate. We propose to identify the progenitor cell populations that functionally require the tlx gene and decipher the molecular and cellular targets of tlx in early and late progenitor cell proliferation and differentiation.
In aim 1 we will use in-vivo lineage analyses to identify the progeny of tlx expressing cells.
In aim 2 we will determine if the composition of progenitor cells or their progeny are altered in the absence of tlx.
In aim 3 we will use chimeric animals to dissect cell autonomous and non-cell autonomous functions of tlx. Finally, in aim 4, we will determine if tlx acts via the notch signal transduction pathway to regulate progenitor cell choice. These studies will provide insights into the genetic pathways regulating proliferation and differentiation in the cerebral cortex and provide insights into the molecular and developmental basis of human neuropsychiatric disorders.
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