Drebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

Trivedi, Niraj; Stabley, Daniel R.; Cain, Blake; Howell, Danielle; Laumonnerie, Christophe; Ramahi, Joseph S.; Temirov, Jamshid; Kerekes, Ryan A.; Gordon‐Weeks, Phillip R.; Solecki, David J.

doi:10.1038/ncomms14484

Cited by 52 publications

(59 citation statements)

References 70 publications

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“…FLPs were observed not only in the V‐SVZ‐derived new neurons (Fig ) but also in other migrating neurons generated in the embryonic ganglionic eminences (Appendix Fig S2). All of these neurons extend a long leading process, in which proximal‐region cytoskeletal changes drive somal translocation (Shinohara et al , ; Yang et al , ; Nishimura et al , ; Ota et al , ; Trivedi et al , ), and distal‐region cytoskeletal changes determine directionality (Martini et al , ; Lysko et al , , ). Since FLPs can develop into lateral dendrites after neuronal migration termination (Appendix Fig S1C and D), the mechanism for FLP formation, which is controlled by Sema3E‐PlexinD1 signaling, could regulate migration termination and the initiation of differentiation, simultaneously and rapidly, providing an efficient strategy for neuronal development.…”

Section: Discussionmentioning

confidence: 99%

PlexinD1 signaling controls morphological changes and migration termination in newborn neurons

et al. 2018

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Newborn neurons maintain a very simple, bipolar shape, while they migrate from their birthplace toward their destinations in the brain, where they differentiate into mature neurons with complex dendritic morphologies. Here, we report a mechanism by which the termination of neuronal migration is maintained in the postnatal olfactory bulb (OB). During neuronal deceleration in the OB, newborn neurons transiently extend a protrusion from the proximal part of their leading process in the resting phase, which we refer to as a filopodium-like lateral protrusion (FLP). The FLP formation is induced by PlexinD1 downregulation and local Rac1 activation, which coincide with microtubule reorganization and the pausing of somal translocation. The somal translocation of resting neurons is suppressed by microtubule polymerization within the FLP The timing of neuronal migration termination, controlled by Sema3E-PlexinD1-Rac1 signaling, influences the final positioning, dendritic patterns, and functions of the neurons in the OB These results suggest that PlexinD1 signaling controls FLP formation and the termination of neuronal migration through a precise control of microtubule dynamics.

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Section: Discussionmentioning

confidence: 99%

PlexinD1 signaling controls morphological changes and migration termination in newborn neurons

et al. 2018

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“…Moreover, the migratory direction of neuroblasts was abnormal in the OB of DXKO mice. These results are consistent with the recent study that drebrin is required for microtubule–actomyosin coupling and steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration (Trivedi et al ., ). Tangential migration is a chain migration that involves close contact of the neuroblasts with each other (Lois & Alvarez‐Buylla, ; Wichterle et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Drebrin E regulates neuroblast proliferation and chain migration in the adult brain

Kajita

Kojima

Koganezawa

et al. 2017

Eur J of Neuroscience

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F-actin-binding protein drebrin has two major isoforms: drebrin A and drebrin E. Drebrin A is the major isoform in the adult brain and is highly concentrated in dendritic spines, regulating spine morphology and synaptic plasticity. Conversely, drebrin E is the major isoform in the embryonic brain and regulates neuronal morphological differentiation, but it is also expressed in neurogenic regions of the adult brain. The subventricular zone (SVZ) is one of the brain regions where adult neurogenesis occurs. Neuroblasts migrate to the olfactory bulb (OB) and integrate into existing neuronal networks, after which drebrin expression changes from E to A, suggesting that drebrin E plays a specific role in neuroblasts in the adult brain. Therefore, to understand the role of drebrin E in the adult brain, we immunohistochemically analyzed adult neurogenesis using drebrin-null-mutant (DXKO) mice. In DXKO mice, the number of neuroblasts and cell proliferation decreased, although cell death remained unchanged. These results suggest that drebrin E regulates cell proliferation in the adult SVZ. Surprisingly, the decreased number of neuroblasts in the SVZ did not result in less neurons in the OB. This was because the survival rate of newly generated neurons in the OB increased in DXKO mice. Additionally, when neuroblasts reached the OB, the change in the migratory pathway from tangential to radial was partly disturbed in DXKO mice. These results suggest that drebrin E is involved in a chain migration of neuroblasts.

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“…The Siah2 E3 ubiquitin ligase appears to act as a central regulator of GZ occupancy by modulating two distinct cell biological processes. Previous results have shown that Siah2 restrains radial migration in progenitors by tagging for ubiquitin-proteasome degradation targets that are required for the pro-migratory adhesive interactions and actin-microtubule crosslinking that are essential for GZ exit and migration along glial fibers (Famulski et al, 2010;Trivedi et al, 2017) . The current study has extended these findings to implicate Siah2 as an active participant in GZ occupancy by supporting primary cilium maintenance in GNPs: Siah2 targets Pard3 and Pifo for degradation, thereby ensuring the reception of signals from the Shh morphogen that promote GNP proliferation at the expense of CGN differentiation.…”

Section: Discussionmentioning

confidence: 99%

Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy

Ong

Trivedi

Wakefield

et al. 2019

Preprint

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Evidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation. We determined that the Siah2 E3 ubiquitin ligase functions in a coincidence detection circuit linking responses to the Shh mitogen and the extracellular matrix to control cerebellar granule neurons (CGN) germinal zone (GZ) occupancy. We found that Shh maintains Siah2 expression in CGN progenitors (GNPs) in a Ras/Mapk-dependent manner. Siah2 supports ciliogenesis in a feed-forward fashion by restraining ciliogenic targets. Efforts to identify GZ sources of Ras/Mapk signaling led us to discover that GNPs respond to laminin, but not vitronectin, in the microenvironment via integrin β1 receptors, which engages the Ras/Mapk cascade, and that this niche interaction is essential for promoting GNP ciliogenesis. As GNPs leave the GZ, differentiation is seamlessly driven by changing extracellular cues that diminish Siah2-activity leading to primary cilia retraction and attenuation of mitogenic responses. Lewis et al., 2004; Wechsler-Reya and Scott, 1999) . This pathway is frequently deregulated to transform GNPs in a distinct subgroup of cerebellar medulloblastomas (Shh-MBs) (Hatten and Roussel, 2011) . The transduction machinery for Shh is localized to the primary cilium, a microtubulebased organelle that is required for the response of GNPs to Shh and, ultimately, for proper cerebellar development (Chizhikov et al., 2009; Satir et al., 2010) . Cilium-localized Patched (Ptch) receptor, the negative regulator of the hedgehog pathway, acts as a repressor of Smoothened (Smo), a G-protein-coupled receptor that is the principal activator of the hedgehog pathway (Rohatgi, 2007) . Binding of the ligand Shh to Ptch relieves its repression of Smo (Qi et al., 2018) , which in turn triggers a series of downstream events that converge into the stabilization and nuclear translocation of the Gli transcription factors (Chen et al., 1999) . Importantly, Shh signaling has ceased by the time differentiated CGNs exit the EGL to undergo radial migration, and despite migrating against a gradient of Shh, the CGNs remain insensitive to the ligand. How developing GNPs turn the Shh pathway on or off and how their responsiveness is modified by local cues, such as pia-derived ECM, is unclear and is a key to understanding how normal and transformed GNPs expand during cerebellar development. CGNs also have a well-characterized cell-intrinsic circuitry controlling GZ exit (Aruga et al., 2002; Famulski et al., 2010; Miyata et al., 1999; Penas et al., 2015; Singh et al., 2016; Trivedi et al., 2017). Prominent among these GZ-exit regulators is the Seven in absentia 2 (Siah2) E3 ubiquitin ligase. This is an evolutionarily conserved cell-fate regulator that is the most downstream component of the Ras GTPase/Map kinase (MAPK) signaling pathway in the specification of R7 cells in the Drosophila retina (Carthew and Rubin, 1990) . Our laboratory has shown that, during CGN differentiation, Siah2 modulates the acqu...

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Drebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

Cited by 52 publications

References 70 publications

PlexinD1 signaling controls morphological changes and migration termination in newborn neurons

PlexinD1 signaling controls morphological changes and migration termination in newborn neurons

Drebrin E regulates neuroblast proliferation and chain migration in the adult brain

Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy

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