| Fibroblast Growth Factor 8 (FGF8) acts as a morphogen to pattern the developing dorsal telencephalon. During neocortical development, FGF8 is secreted from a source near the anterior pole of the telencephalon, disperses across the whole of the neocortical primordium, and forms an exponentially declining concentration gradient across the anterior-to-posterior axis of this tissue. This concentration gradient fosters the expression of different genes at different locations along the anterior-to-posterior axis of the neocortex. Ultimately, these changes in gene expression produce, through as yet unclear mechanisms, the mature neocortical area map.;A classical morphogen model might suggest that a morphogen, like FGF8, must operate through a single intracellular signal transduction cascade and induce or suppress downstream genetic targets in a morphogen concentration dependent manner. Results supporting this idea were found for a subset of genes that were induced by FGF8 early within the transcriptional regulatory cascade. However, the vast majority of genes regulated by FGF8 did not adhere to the expectations associated with a classical morphogen model. Rather, the data in this thesis demonstrate that the morphogen-like activities of FGF8 in the neocortical primordium share many of the same complexities and regulatory mechanisms seen in other developmental patterning systems.;I found that both the MEK/ERK and PI3K/AKT signal transduction cascades operate downstream of FGF8 to pattern the neocortical primordium. However, the activation and function of these cascades was both qualitatively and quantitatively distinct. ERK phosphorylation was induced in an FGF8 concentration dependent manner and MEK/ERK activation tended to induce the expression of genes known to be involved in neocortical patterning, often in a phosphorylated ERK concentration dependent manner. Conversely, AKT phosphorylation is induced by FGF8 in an FGF8 concentration independent manner. Additionally, those genes known to be downstream targets involved in neocortical patterning and induced by FGF8 were found to be induced through the MEK/ERK signal transduction cascade. However, known participants in neocortical patterning known to be downstream of FGF8 and suppressed by FGF8 were suppressed through the PI3K/AKT signal transduction cascade. Finally, multiple examples of both collaboration and competition between the MEK/ERK and PI3K/AKT signal transduction cascades, both at the level of genes and biological processes, were observed.;The discovery that the PI3K/AKT signal transduction cascade contributes to the regulation of genes involved in neocortical patterning is a significant novel finding. It is also, in a sense, a blow against the classical morphogen model. Assuming FGF8 to be a classical morphogen allowed a number of predictions regarding neocortical patterning to be made while precluding several alternate possibilities. This thesis clearly demonstrates the limitations of the classical morphogen model in the context of the neocortical primordium and, by so doing, fundamentally alters standard conceptions and expectations concerning the development of that tissue. |
