THESIS
2012
xviii, 109 p. : ill. (some col.) ; 30 cm
Abstract
Proper functioning of the nervous system depends on the correct positioning of neurons,
establishment of axon-dendrite polarity, formation of neural circuits and maintenance of the
wired neural circuits. These steps are critically controlled by various molecular signaling
pathways. Defect in any of these processes greatly impair neural functions. In particular, defects
in neuronal migration are associated with various neurological disorders in human including
lissencephaly (smooth brain), cortical heterotopias (double cortex), microcephaly (small brain)
and autism (Gleeson, 2000; Hashimoto-Torii et al., 2008; Manent et al., 2009). These clinical
observations highlight the importance of the precise neuronal positioning and organization during
the development of the nervous system...[
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Proper functioning of the nervous system depends on the correct positioning of neurons,
establishment of axon-dendrite polarity, formation of neural circuits and maintenance of the
wired neural circuits. These steps are critically controlled by various molecular signaling
pathways. Defect in any of these processes greatly impair neural functions. In particular, defects
in neuronal migration are associated with various neurological disorders in human including
lissencephaly (smooth brain), cortical heterotopias (double cortex), microcephaly (small brain)
and autism (Gleeson, 2000; Hashimoto-Torii et al., 2008; Manent et al., 2009). These clinical
observations highlight the importance of the precise neuronal positioning and organization during
the development of the nervous system. Nonetheless, little is known about how neuronal
migration is regulated in vivo and the molecular mechanisms underlying the regulation of
neuronal polarization during neuronal migration remain to be elucidated. Signaling proteins that
regulate cytoskeletal dynamics are suggested to be involved in neuronal polarization and
migration.
In the present study, I identify α2-chimaerin as an essential regulator in neuronal
migration and laminar positioning of the cortex. α2-chimaerin is highly expressed in the
intermediate zone (IZ) and cortical plate (CP) of the cerebral cortex during developmental stage.
Knockdown of α2-chimaerin in utero arrests neurons in the IZ with abnormal polarity. By live-imaging
analysis, I show that α2-chimaerin regulates the multipolar-to-bipolar transition of
migrating neurons. α2-chimaerin-depleted neurons show reduced neurite dynamics as well as
impaired neuronal migration. Knockdown of α2-chimaerin in utero leads to the formation of a heterotopic band of neurons in the subcortical white matter in postnatal mice. Mice with such
migration defects display imbalanced excitation/inhibition of local cortical circuitry, and exhibit
increased susceptibility to convulsant-induced seizures. I further demonstrate the functional
importance of the SH2 domain-mediated association of α2-chimaerin in neuronal migration. α2-chimaerin binds to Trk receptors and modulates neurotrophin-mediated Trk signaling.
Importantly, α2-chimaerin regulates bipolar transition and neuronal migration through
modulating the activity of collapsin response mediator protein-2 (CRMP-2), a microtubule-associated
protein. These findings establish a new α2-chimaerin-dependent mechanism
underlying neuronal migration and proper functioning of the cerebral cortex, and provide
significant insights into understanding the pathogenesis of seizure-related neurodevelopmental
disorders.
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