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.

Notch4 inhibition reduces migration and invasion and enhances sensitivity to docetaxel by inhibiting Akt/fascin in pancreatic cancer cells

“…Of note, it was observed that the downregulation of Notch4 reduced the expression of fascin. Several studies reported that fascin significantly increases cell migration by enhancing the directional motility of cells (33). The present study demonstrated that the downregulation of Notch4 decreased the expression of fascin, suggesting that Notch4 may regulate cell migration, at least by fascin.…”

RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development

“…5), which is likely to affect their fate and synaptic integration, as in the case of another migration regulator, doublecortin (Belvindrah et al, 2011). RMS neuroblast migration is saltatory, alternating process extension with nucleokinesis, with a very dynamic leading protrusion (Nam et al, 2007;Sonego et al, 2013b). Interestingly, perturbing the RalA-Exo84 interaction impaired neuroblast migration, and caused both process loss and misorientation.…”

Fascin – An actin binding and bundling protein in the testis and its role in ectoplasmic specialization dynamics

“…18 A careful examination of these fascin 1 ¡/¡ mice have shown that they possess smaller olfactory bulb due to defects in the migration of neuroblasts in the brain during postnatal development. 19 These findings using a genetic model in the mouse suggest that while the function of fascin 1 can be superseded by other actin bundling proteins, such as fascin 2 and others (e.g., palladin, Eps8, ezrin), fascin 1 is important to confer mobility to neuroblasts that migrate along the rostral migratory stream to become interneurons in the olfactory bulb in developing brain, 18 and its deletion in humans could still lead to infertility or subfertility. Other studies in non-neuronal cells have shown that fascin is associated with a number of extracellular matrix (ECM) proteins such as thrombospondin-1 and fibronectin, and cell adhesion molecules such as integrins and syndecan-1.…”