Disturbances in Progenitor Cell Placement, Proliferation, and Apoptosis Modify Neocortical Development in the Tish Neurogical Mutant

Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. In one such malformation, subcortical band heterotopia (SBH), large numbers of cortical neurons and glia are improperly located in a discreet band in the subcortical white matter. While theories focusing on defective neuronal migration have yielded causative genes and pathogenic mechanisms for certain human cases of this disorder, others still exist for which no causative genetic or cellular disturbances can be identified, leaving open the possibility for alternative mechanisms of SBH formation. The tish rat is spontaneously occurring genetic model of SBH in which the malformation is inherited in an autosomal recessive manner. A unique feature of developing tish -/- neocortex, which has not been reported in other animal models of SBH, is the presence of an abnormally located (heterotopic) band of proliferating cells in the intermediate zone and cortical plate in addition to the normally positioned progenitors in the ventricular and subventricular zones. The guiding hypothesis of this thesis is that heterotopic proliferative cells contribute to the formation of the tish -/- SBH. The experiments presented herein characterize the identity and cell cycle kinetics of these heterotopic proliferating cells and investigate the cellular mechanism underlying their mislocalization. Overall, the results demonstrate that the tish mutation disrupts the position and cell cycle kinetics of progenitors of the radial glial and intermediate progenitor lineages in the developing neocortex. This mislocalization is not associated with adherens junction breakdown or ii loss of radial glial polarity in the ventricular zone. The mislocalized progenitors in tish -/- neocortex do not appear to maintain contact with the ventricular surface. Therefore, the affected progenitor cells may be unable to exit the cell cycle once they initiate migration, which leads to the seeding of a heterotopic proliferative zone upon their arrival in the IZ/CP. Taken together, these findings define a form of developmental error contributing to SBH formation that differs fundamentally from a primary error in neuronal migration.

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