Cerebral cortex development is a complex process that integrates both extrinsic and intrinsic mechanisms. The surrounding cellular environment triggers receptor activation, which in turn initiates components of different signalling cascades and subsequently gene transcription, influencing cell survival, proliferation, and differentiation. Genetic mutations causing a loss-of-function or gain-of-function of signalling pathways elements can lead to cortical abnormalities and result in cognitive dysfunctions. In this thesis, I examined the receptor tyrosine kinase (RTK) TrkB and TrkC, the small GTPase Ras, and the C/EBP family of transcription factors, investigating their roles during cerebral cortex development. First, I looked at the role of C/EBPs during cortical cell fate determination. I determined that inhibition of C/EBPs decrease neurogenesis, keeping precursors in an undifferentiated state and later promoting their differentiation into astrocytes, while expression of an activated form of C/EBP promoted neurogenesis and reduced astrogenesis. Moreover, the inhibition of MEK, a mediator of C/EBPβ phosphorylation, also caused a decrease in neurogenesis. Thus, activation of the MEK-C/EBP pathway biases precursor cells to become neurons rather than astrocytes, thereby acting as a differentiation switch. Second, I examined the involvement of Trk signalling during cortical development. I showed that genetic knockdown using shRNA, or inhibition using dominant negative of TrkB and TrkC lead to a decrease in proliferation and later to postnatal precursor cells depletion. Moreover, it caused a reduction in number of neurons combined with mislocalization of the generated neurons to the different cortical layers. Thus, Trk signalling plays an essential role in the regulation of cortical precursor cell proliferation and differentiation during embryonic development. Third, I elucidated the effect of Costello syndrome H-Ras mutations during cerebral cortex formation. I determined that these mutations promoted cell proliferation and astrogenesis, while reducing neurogenesis. Together, these data support a model where proper Trks/Ras/MEK/C/EBP signalling is essential for normal genesis of neurons and astrocytes and show that cortical development perturbations can ultimately lead to cognitive dysfunction as seen in Costello syndrome patients.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/19292 |
| Date | 03 March 2010 |
| Creators | Paquin, Annie |
| Contributors | Miller, Freda |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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