The Effects of Drebrin in Postnatal Neuroblast Migration

Postnatal neurogenesis, a process linked to memory, mood and learning persists in two main niches in the mammalian brain: the hippocampal dentate gyrus and the subventricular zone (SVZ). SVZ-derived neural progenitors migrate tangentially along the rostral migratory stream (RMS) towards the olfactory bulb (OB) where they differentiate into interneurons. Although several cell adhesion molecules, growth factors, axon guidance receptors, and neurotransmitters control neural progenitor migration, how these cues couple with intracellular signaling pathways is still unclear. Understanding the molecular mechanisms underlying neural progenitor migration may grant insight in developing therapeutic approaches to repair the nervous system. The actin filament-binding protein drebrin couples microtubules to filopodia. We found that drebrin is highly expressed in growth cones of migrating neuroblasts in the RMS, and that drebrin knockdown disrupts neuroblast polarized morphology and migration. Cdk5-dependent phosphorylation of drebrin at Serine-142 was recently shown to regulate microtubule-F-actin coupling. Our goal is to uncover the functional role of this phosphorylation in neuroblast migration by using phospho-dead (S142A) and phosphomimetic (S142D) constructs. We performed in vivo postnatal electroporation of GFP-tagged S142A and S142D drebrin constructs in mice coupled with spinning disk confocal microscopy of acute brain slice cultures and RMS explants. Quantitative analysis of neuroblast morphology and migration dynamics indicates that in vivo overexpression of drebrin wildtype, S142A, and S142D significantly disrupts neuroblast morphology and polarity, substantially impeding migration along the RMS and integration in the OB. Our analysis suggests that phosphorylation at S142 must be tightly regulated for proper migration of SVZ-derived neural progenitors.