title: Fascin regulates the migration of subventricular zone-derived neuroblasts in the postnatal 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 a fundamental event controlling the proper integration of new neurons in a pre-existing synaptic network. Many regulators of neuroblast migration have been identified; however, still very little is known about the intracellular molecular mechanisms controlling this process. Here, we show that the actin-bundling protein fascin is highly upregulated in mouse SVZ-derived migratory neuroblasts. Fascin-1ko mice display an abnormal RMS and a smaller OB. Bromodeoxyuridine labeling experiments show that lack of fascin significantly impairs neuroblast migration, but does not appear to affect cell proliferation. Moreover, fascin depletion substantially alters the polarized morphology of rat neuroblasts. Protein kinase C (PKC)-dependent phosphorylation of fascin on Ser39 regulates its actin-bundling activity. In vivo postnatal electroporation of phosphomimetic (S39D) or nonphosphorylatable (S39A) fascin variants followed by time-lapse imaging of brain slices demonstrates that the phospho-dependent modulation of fascin activity ensures efficient neuroblast migration. Finally, fluorescence lifetime imaging microscopy studies in rat neuroblasts reveal that the interaction between fascin and PKC can be modulated by cannabinoid signaling, which controls neuroblast migration in vivo. We conclude that fascin, whose upregulation appears to mark the transition to the migratory neuroblast stage, is a crucial regulator of neuroblast motility. We propose that a tightly regulated phospho/dephospho-fascin cycle modulated by extracellular signals is required for the polarized morphology and migration in neuroblasts, thus contributing to efficient neurogenesis.
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Sonego
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Gajendra
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Ma
authors.forename: Carl
authors.initials: C
authors.lastname: Hobbs
authors.forename: Marc P
authors.initials: MP
authors.lastname: Zentar
authors.forename: Gareth
authors.initials: G
authors.lastname: Williams
authors.forename: Laura M
authors.initials: LM
authors.lastname: Machesky
authors.forename: Patrick
authors.initials: P
authors.lastname: Doherty
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lalli
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D007395:Interneurons / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology*; D009830:Olfactory Bulb / Q000002:abnormalities / Q000166:cytology / Q000254:growth & development*; D010766:Phosphorylation / Q000502:physiology; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018035:Receptors, Odorant; D015398:Signal Transduction / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology
chemical_list: D002186:Cannabinoids; D008840:Microfilament Proteins; D011493:Protein Kinase C; D018035:Receptors, Odorant; C535054:Fscn1 protein, rat; C544141:Olfr73 protein, mouse