Characterizing the functional roles of α2-chimaerin in the development of cerebral cortex

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. 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.

Date of Award	2012
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology