THESIS
2013
xvii, 143, [33] pages : illustrations (some color) ; 30 cm
Abstract
The functional wiring of the cerebral cortex requires multiple coordinated steps of
neuronal migration; the perturbation of which leads to brain malformation and various
neuropsychiatric disorders such as epilepsy and schizophrenia. Rap1, a small GTPase,
regulates multiple important steps of migration, including multipolar–bipolar transition and
somal translocation. However, how Rap1 is differentially regulated during these phases is
poorly understood. The present study demonstrates that the guanine nucleotide exchange
factor, RapGEF2, but not RapGEF1 (also known as C3G), is required for multipolar–bipolar transition in a Rap1-dependent manner. In utero suppression of RapGEF2 arrested
neuronal migration in the multipolar stage, ultimately resulting in subcortical band
formation...[
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The functional wiring of the cerebral cortex requires multiple coordinated steps of
neuronal migration; the perturbation of which leads to brain malformation and various
neuropsychiatric disorders such as epilepsy and schizophrenia. Rap1, a small GTPase,
regulates multiple important steps of migration, including multipolar–bipolar transition and
somal translocation. However, how Rap1 is differentially regulated during these phases is
poorly understood. The present study demonstrates that the guanine nucleotide exchange
factor, RapGEF2, but not RapGEF1 (also known as C3G), is required for multipolar–bipolar transition in a Rap1-dependent manner. In utero suppression of RapGEF2 arrested
neuronal migration in the multipolar stage, ultimately resulting in subcortical band
formation in the postnatal mouse brain. Furthermore, the GEF activity of RapGEF2 and
subsequent Rap1 activation require phosphorylation by the serine/threonine kinase, cyclin-dependent
kinase-5 (Cdk5). Thus, the present results demonstrate that the Cdk5-dependent
activation of RapGEF2, spatial activation of Rap1 signaling, and Rap1-facilitated surface
localization of N-cadherin in the intermediate zone control neuronal migration and
ultimately the architecture of the mammalian cerebral cortex. Furthermore, RapGEF2 plays
an intriguing role in Rap1 activation, specifically in multipolar–bipolar transition; this
contrasts with the proposed role of C3G in somal translocation. These findings provide an
integrated understanding of how multiple migration phases are differentially regulated by a
common molecular switch.
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