Molecular Mechanisms Regulating Fate Determination of Cerebral Cortex Precursors

During development of the mammalian nervous system, neural stem cells generate neurons first and glia second, thereby allowing the initial establishment of neuronal circuitry, and subsequent matching of glial numbers and position to that circuitry. Multiple molecular mechanisms act in concert to control neural precursor expansion prior to neurogenesis, and to allow for an exponential generation of neurons while ensuring the maintenance of sufficient precursors to produce later-born neurons, glial cells and adult neural stem cells. Throughout cortical development, these processes are regulated in part by the precursors’ environment as well as intrinsic changes in precursors and their modes of division, which regulate the fate of daughter cells and the balance between self-renewal and differentiation. In the first part of this thesis, the protein tyrosine phosphatase SHP-2 was identified as a novel signaling protein that regulates the neurogenic to gliogenic switch by potentiating neurogenic signals and suppressing gliogenic signals until the appropriate developmental time point for astrogenesis, providing one mechanism whereby precursors integrate conflicting environmental cues. A Noonan Syndrome (NS)-associated activated SHP-2 mutation causes perturbations in neural cell genesis, which may contribute to the mild mental retardation and learning disabilities observed in NS patients. In the second part of this thesis, a novel Rho-regulatory pathway which includes the Rho-GEF Lfc and its negative regulator Tctex-1 were also found to regulate neurogenesis, potentially by directing mitotic spindle orientation during precursor divisions, thereby regulating the symmetric and asymmetric nature of radial precursor divisions.Ph