Distinguishing between Directional Guidance and Motility Regulation in Neuronal Migration

Ward, Michael E.; McCann, Corey M.; DeWulf, Michael; Wu, Jane Y.; Rao, Yi

doi:10.1523/jneurosci.23-12-05170.2003

Cited by 58 publications

(78 citation statements)

References 39 publications

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“…Many intracellular signaling pathways are activated by guidance cues and induce cytoskeletal reorganization in growth cones and leading processes (33,34). This cytoskeletal dynamic is essential for growth cone turning during pathfinding and for deciding in which direction a cell migrates (33)(34)(35). The existence of multiple regulatory mechanisms such as phosphorylation by several different kinases (13)(14)(15) and neurabin II would contribute to the ability of Dcx to respond to a wide range of guidance cues during cortical development.…”

Section: Discussionmentioning

confidence: 99%

Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Tsukada

Prokscha

Ungewickell

et al. 2005

Journal of Biological Chemistry

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Mutations in the human Doublecortin (DCX) gene cause X-linked lissencephaly, a neuronal migration disorder affecting the neocortex and characterized by mental retardation and epilepsy. Because dynamic cellular asymmetries such as those seen in cell migration critically depend on a cooperation between the microtubule and actin cytoskeletal filament systems, we investigated whether Dcx, a microtubule-associated protein, is engaged in cytoskeletal cross-talk. We now demonstrate that Dcx co-sediments with actin filaments (F-actin), and using light and electron microscopy and spin down assays, we show that Dcx induces bundling and crosslinking of microtubules and F-actin in vitro. It has recently been shown that binding of Dcx to microtubules is negatively regulated by phosphorylation of the Dcx at Ser-47 or Ser-297. Although the phosphomimetic green fluorescent protein (GFP)-Dcx S47E transfected into COS-7 cells had a reduced affinity for microtubules, we found that pseudophosphorylation was not sufficient to cause Dcx to bind to F-actin. When cells were co-transfected with neurabin II, a protein that binds F-actin as well as Dcx, GFP-Dcx and to an even greater extent GFP-Dcx S47E became predominantly associated with filamentous actin. Thus Dcx phosphorylation and neurabin II combinatorially enhance Dcx binding to F-actin. Our findings raise the possibility that Dcx acts as a molecular link between microtubule and actin cytoskeletal filaments that is regulated by phosphorylation and neurabin II.

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Section: Discussionmentioning

confidence: 99%

Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Tsukada

Prokscha

Ungewickell

et al. 2005

Journal of Biological Chemistry

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“…In order to test this, we monitored migration of neurons exiting P5 Dcx +/y and -/y SVZa explants in vitro. In the wt, there was robust migration away from the explant over the 12-hour timecourse of the experiment 17,39 . Parallel experiments performed with mutant explants showed a severe reduction in neuronal migration, without an apparent effect on cell exit from the explant (Fig.…”

Section: Decreased Migration Of Neurons Exiting Svza But No Apparent mentioning

confidence: 99%

“…Uniform parasagittal 300 µm brain sections (MX-TS Tissue Slicer) were mounted in a 1:1 collagen /culture media mixture, stabilized for several hours, then subject to multiphoton microscopy. DiI labeling was performed as reported 39 , except that after 12-hour incubation, slices immobilized in collagen gel and subject to multiphoton microscopy. SVZa explants.…”

Section: Plays An Essential Role In Maintaining Bipolar Morphologymentioning

confidence: 99%

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Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

et al. 2006

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The ability of the mature mammalian nervous system to continually produce neuronal precursors is of considerable importance, as manipulation of this process might one day permit the replacement of cells lost as a result of injury or disease. In mammals, the anterior subventricular zone (SVZa) region is one of the primary sites of adult neurogenesis. Here we show that Doublecortin (DCX), a widely used marker for newly generated neurons, when deleted in mouse results in a severe morphological defect in the rostral migratory stream and delayed neuronal migration that is independent of direction or responsiveness to Slit chemorepulsion. DCX is required for nuclear translocation and maintenance of bipolar morphology during migration of these cells. Our data identifies a critical function for DCX in the movement of newly generated neurons in the adult brain.In the rodent and primate brain, the anterior region of the lateral ventricle and the hippocampus are the primary sites of adult neurogenesis [1][2][3][4][5][6][7] . These neuroblasts, upon completing migration, are capable of maturing into fully differentiated neurons, integrating into local synaptic circuits and may be important in adult cognitive processing [8][9][10][11] .The mechanisms controlling the targeted translocation of large numbers of cells to the olfactory bulb (OB) over a considerable distance (>5 mm in the adult mouse) are an issue of intense investigation. These neurons translocate using a process known as chain migration, whereby the cells use each other as the migratory substrate 12 . These newly generated neurons are derived from SVZa glial fibrillary acidic protein (GFAP)-positive astrocytes 13,14 , which also ensheath them as they move through extensive interconnected networks along the lining of the lateral ventricle in the rostral forebrain and the rostral migratory stream (RMS) 15 . There, they are under the control of extracellular migration guidance cues, including the secreted ligands Slit and Reelin [16][17][18][19] , the receptors ErbB4 and Deleted in Colorectal Carcinoma (DCC) 20,21 , as well as integrins and neural cell adhesion molecule [21][22][23] . Upon reaching the bulb, the neurons turn and migrate in a radial direction 24 , integrating into either the granule cell layer or the periglomerular network 25 . 3The X-linked gene doublecortin (DCX) is mutated in some patients with the severe neuronal migration defect called classical lissencephaly or double cortex syndrome 26,27 . This migration defect is likely to be cell autonomous, because in females with a heterozygous mutation, approximately half of the neurons are misplaced within the cerebral cortex as would be expected from random X-chromosome inactivation. As a result, males display a four-layered agyric cortex and females display a subcortical band of heterotopic neurons. It was surprising, therefore, that the Dcx knockout mice displayed no appreciable defect in cortical neuronal lamination or positioning 28 . One possible explanation for these species differences ...

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“…Directional migration cues, which are relevant following neural injury, include members of the chemokine family, such as CXCL12/CXCR4 [14][15][16]. Axon guidance molecules, such as Slits [17,18] and other factors [19,20], also play a role in the directed NPC migration along the RMS, along with chemoattractive agents secreted from the OB such as sonic hedgehog [21] or secreted or membranebound factors on the astrocytic glial tube that surrounds the NPCs in the RMS [22,23].…”

Section: Introductionmentioning

confidence: 99%

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

et al. 2011

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Adult neural precursor cells (NPCs) in the subventricular zone (SVZ) normally migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB). Following neural injury, they also migrate to the site of damage. This study investigated the role of Rho-dependent kinase (ROCK) on the migration of NPCs in vitro and in vivo. In vitro, using neurospheres or SVZ explants, inhibition of ROCK using Y27632 promoted cell body elongation, process protrusion, and migration, while inhibiting NPC chain formation. It had no effect on proliferation, apoptosis, or differentiation. Both isoforms of ROCK were involved. Using siRNA, knockdown of both ROCK1 and ROCK2 was required to promote NPC migration and morphological changes; knockdown of ROCK2 alone was partially effective, with little/no effect of knockdown of ROCK1 alone. In vivo, infusion of Y27632 plus Bromodeoxyuridine (BrdU) into the lateral ventricle for 1 week reduced the number of BrdU-labeled NPCs in the OB compared with BrdU infusion alone. However, ROCK inhibition did not affect the tangential-to-radial switch of NPC migration, as labeled cells were present in all OB layers. The decrease in NPC number at the OB was not attributed to a decrease in NPCs at the SVZ. However, ROCK inhibition decreased the density of BrdU-labeled cells in the RMS and increased the distribution of these cells to ectopic brain regions, such as the accessory olfactory nucleus, where the majority differentiated into neurons. These findings suggest that ROCK signaling regulates NPC migration via regulation of cell-cell contact and chain migration.

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Distinguishing between Directional Guidance and Motility Regulation in Neuronal Migration

Cited by 58 publications

References 39 publications

Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

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