Molecular mechanisms regulating cortical development

The generation of the mammalian nervous system occurs via a series of integrated developmental processes, beginning with the induction and patterning of neurogenic regions and the formation of progenitor cells, which give rise to neurons and glia. These early events are followed by periods of neuronal migration, axon guidance, and synaptogenesis. Ultimately, these processes result in a functioning nervous system that is continually modified in an experience-dependent fashion to allow the organism to learn from and adapt to its environment. The findings presented in this dissertation focus on two steps of this complex developmental program, first studying the role of Ror-family receptor tyrosine kinases in regulating neocortical neurogenesis, and then examining the role of the Rac1 guanine nucleotide exchange factor Tiam1 in NMDA receptor-dependent structural remodeling of synapses. Cortical neurogenesis occurs in a stereotyped fashion, during which neural progenitor cells (NPCs) in the ventricular zone divide to generate successive layers of neurons. We show that Ror2, a receptor for Wnt5a, is highly expressed in the developing cortex. In particular, Ror2 expression is restricted to the ventricular zone of the dorsal telencephalon, the region of the cortex that gives rise to excitatory glutamatergic projection neurons. Using two independent lines of mice with targeted mutations in Ror2, we find that Ror2-deficient NPCs cultured in vitro exhibit an increased rate of neural differentiation as assessed by immunostaining with the neuronal marker TuJ1. Quantitative real-time PCR to measure mRNA expression also showed a significant increase in TuJ1 levels from neural progenitors lacking functional Ror2. These findings identify a novel role for Ror2 in the regulation of neural development and suggest a potential mechanism for Wnt-mediated neurogenesis in the cortex. Perhaps the most amazing aspect of the nervous system is its ability to be modified in response to experience in an activity-dependent manner. NMDA-type glutamate receptors are known to play a critical role in the structural and functional plasticity of dendritic spines and arbors, but the mechanisms linking NMDA receptor activation to changes in spine morphogenesis are unclear. We show that the Rac1 guanine nucleotide exchange factor Tiam1 is expressed in dendrites and spines and is required for their development. Tiam1 interacts with the NMDA receptor, and upon NMDA receptor activation Tiam1 becomes phosphorylated in a calcium-dependent manner. Interfering with Tiam1 function via expression of dominant-interfering mutants or short hairpin RNAs suggests that Tiam1 mediates the effects of NMDA receptor activation via Rac1-dependent actin remodeling and protein synthesis. Taken together, the work presented in this dissertation addresses how developmental signals regulate aspects of neurogenesis in the cortex, and elucidates a mechanism through which NMDA receptor activation contributes to the structural remodeling of synapses.