title: Drebrin regulates neuroblast migration in the postnatal mammalian brain.
abstract: After birth, stem cells in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) to become interneurons in the olfactory bulb (OB). This migration is crucial for the proper integration of newborn neurons in a pre-existing synaptic network and is believed to play a key role in infant human brain development. Many regulators of neuroblast migration have been identified; however, still very little is known about the intracellular molecular mechanisms controlling this process. Here, we have investigated the function of drebrin, an actin-binding protein highly expressed in the RMS of the postnatal mammalian brain. Neuroblast migration was monitored both in culture and in brain slices obtained from electroporated mice by time-lapse spinning disk confocal microscopy. Depletion of drebrin using distinct RNAi approaches in early postnatal mice affects neuroblast morphology and impairs neuroblast migration and orientation in vitro and in vivo. Overexpression of drebrin also impairs migration along the RMS and affects the distribution of neuroblasts at their final destination, the OB. Drebrin phosphorylation on Ser142 by Cyclin-dependent kinase 5 (Cdk5) has been recently shown to regulate F-actin-microtubule coupling in neuronal growth cones. We also investigated the functional significance of this phosphorylation in RMS neuroblasts using in vivo postnatal electroporation of phosphomimetic (S142D) or non-phosphorylatable (S142A) drebrin in the SVZ of mouse pups. Preventing or mimicking phosphorylation of S142 in vivo caused similar effects on neuroblast dynamics, leading to aberrant neuroblast branching. We conclude that drebrin is necessary for efficient migration of SVZ-derived neuroblasts and propose that regulated phosphorylation of drebrin on S142 maintains leading process stability for polarized migration along the RMS, thus ensuring proper neurogenesis.
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Sonego
authors.affiliation: Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Oberoi
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Jake
authors.initials: J
authors.lastname: Stoddart
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Gajendra
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Rita
authors.initials: R
authors.lastname: Hendricusdottir
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Fazal
authors.initials: F
authors.lastname: Oozeer
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Worth
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Carl
authors.initials: C
authors.lastname: Hobbs
authors.affiliation: Cluster of Excellence NeuroCure and Institute of Biochemistry, Charité -Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Britta J
authors.initials: BJ
authors.lastname: Eickholt
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Gordon-Weeks
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Doherty
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lalli
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D018274:Electroporation; D005260:Female; D006801:Humans; D020547:Lateral Ventricles / Q000166:cytology* / Q000254:growth & development; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D009479:Neuropeptides; D034741:RNA, Small Interfering; C083795:drebrin E; C053386:drebrins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse