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.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17765 |
| Date | 24 September 2009 |
| Creators | Gauthier, Andree S. |
| Contributors | Miller, Freda, Kaplan, David |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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