Identification of functional marker proteins in the mammalian growth cone

Nozumi, Motohiro; Togano, Tetsuya; Takahashi-Niki, Kazuko; Jia, Lan; Honda, Atsuko; Taoka, Masato; Shinkawa, Takashi; Koga, Hisashi; Takeuchi, Kosei; Isobe, Toshiaki; Igarashi, Michihiro

doi:10.1073/pnas.0904092106

Cited by 84 publications

(117 citation statements)

References 44 publications

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“…These results agree with the presence of SynCAM 1 in growth cone preparations (Fig. S2) and with the recent proteomic identification of SynCAM 1 as a strongly enriched growth cone protein (22).…”

Section: Resultssupporting

confidence: 81%

SynCAM 1 participates in axo-dendritic contact assembly and shapes neuronal growth cones

Stagi

Fogel

Biederer

2010

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal growth cones are highly motile structures that tip developing neurites and explore their surroundings before axo-dendritic contact and synaptogenesis. However, the membrane proteins organizing these processes remain insufficiently understood. Here we identify that the synaptic cell adhesion molecule 1 (SynCAM 1), an immunoglobulin superfamily member, is already expressed in developing neurons and localizes to their growth cones. Upon interaction of growth cones with target neurites, SynCAM 1 rapidly assembles at these contacts to form stable adhesive clusters. Synaptic markers can also be detected at these sites. Addressing the functions of SynCAM 1 in growth cones preceding contact, we determine that it is required and sufficient to restrict the number of active filopodia. Further, SynCAM 1 negatively regulates the morphological complexity of migrating growth cones. Focal adhesion kinase, a binding partner of SynCAM 1, is implicated in its morphogenetic activities. These results reveal that SynCAM 1 acts in developing neurons to shape migrating growth cones and contributes to the adhesive differentiation of their axo-dendritic contacts.

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Section: Resultssupporting

confidence: 81%

SynCAM 1 participates in axo-dendritic contact assembly and shapes neuronal growth cones

Stagi

Fogel

Biederer

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Of the proteins that we identified as growth cone constituents by tandem mass spectrometry, 85% overlap with those identified in a recent study of biochemically isolated growth cone particle fraction from rat forebrain (Nozumi et al, 2009). Both approaches identified 14-3-3 , ␥, and as growth cone constituents while Nozumi and colleagues additionally identified 14-3-3␤ and .…”

Section: -3-3 Expression In Growth Conesmentioning

confidence: 53%

14-3-3 Proteins Regulate Protein Kinase A Activity to Modulate Growth Cone Turning Responses

Kent¹,

Shimada²,

Ferraro³

et al. 2010

J. Neurosci.

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Growth cones regulate the speed and direction of neuronal outgrowth during development and regeneration. How the growth cone spatially and temporally regulates signals from guidance cues is poorly understood. Through a proteomic analysis of purified growth cones we identified isoforms of the 14-3-3 family of adaptor proteins as major constituents of the growth cone. Disruption of 14-3-3 via the R18 antagonist or knockdown of individual 14-3-3 isoforms switches nerve growth factor-and myelin-associated glycoproteindependent repulsion to attraction in embryonic day 13 chick and postnatal day 5 rat DRG neurons. These effects are reminiscent of switching responses observed in response to elevated cAMP. Intriguingly, R18-dependent switching is blocked by inhibitors of protein kinase A (PKA), suggesting that 14-3-3 proteins regulate PKA. Consistently, 14-3-3 proteins interact with PKA and R18 activates PKA by dissociating its regulatory and catalytic subunits. Thus, 14-3-3 heterodimers regulate the PKA holoenzyme and this activity plays a critical role in modulating neuronal responses to repellent cues.

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“…However, from our observations it appears that HSV-1 pUS9 via the KDB plays a major role in anterograde axonal transport and neuronal spread from the distal axon. These processes would require interactions with cytoskeletal transport proteins, such as kinesin-1, as well as vesicular trafficking proteins or proteins involved in exocytosis which are enriched in growth cones (50)(51)(52). We have previously identified such classes of proteins, including Rab3A, SNAP-25, GAP-43, and kinesin-1, colocalizing with HSV-1 virions in growth cones (36).…”

Section: Discussionmentioning

confidence: 99%

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Diefenbach

Davis

Miranda-Saksena

et al. 2016

J Virol

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The alphaherpesviral envelope protein pUS9 has been shown to play a role in the anterograde axonal transport of herpes simplex virus 1 (HSV-1), yet the molecular mechanism is unknown. To address this, we used an in vitro pulldown assay to define a series of five arginine residues within the conserved pUS9 basic domain that were essential for binding the molecular motor kinesin-1. The mutation of these pUS9 arginine residues to asparagine blocked the binding of both recombinant and native kinesin-1. We next generated HSV-1 with the same pUS9 arginine residues mutated to asparagine (HSV-1pUS9KBDM) and then restored them being to arginine (HSV-1pUS9KBDR). The two mutated viruses were analyzed initially in a zosteriform model of recurrent cutaneous infection. The primary skin lesion scores were identical in severity and kinetics, and there were no differences in viral load at dorsal root ganglionic (DRG) neurons at day 4 postinfection (p.i.) for both viruses. In contrast, HSV-1pUS9KBDM showed a partial reduction in secondary skin lesions at day 8 p.i. compared to the level for HSV-1pUS9KBDR. The use of rat DRG neuronal cultures in a microfluidic chamber system showed both a reduction in anterograde axonal transport and spread from axons to nonneuronal cells for HSV-1pUS9KBDM. Therefore, the basic domain of pUS9 contributes to anterograde axonal transport and spread of HSV-1 from neurons to the skin through recruitment of kinesin-1. IMPORTANCEHerpes simplex virus 1 and 2 cause genital herpes, blindness, encephalitis, and occasionally neonatal deaths. There is also increasing evidence that sexually transmitted genital herpes increases HIV acquisition, and the reactivation of HSV increases HIV replication and transmission. New antiviral strategies are required to control resistant viruses and to block HSV spread, thereby reducing HIV acquisition and transmission. These aims will be facilitated through understanding how HSV is transported down nerves and into skin. In this study, we have defined how a key viral protein plays a role in both axonal transport and spread of the virus from nerve cells to the skin. Deletion of the US9 gene, encoding the conserved type II transmembrane viral envelope protein pUS9 (1) (Fig. 1), has been undertaken in a range of Alphaherpesvirinae subfamily members, and neuronal spread has been assessed in several biological models. The relative contribution of pUS9 to neuronal spread within this subfamily was found to differ. Equine herpesvirus type 1 (EHV-1) and bovine herpesvirus type 1 (BHV-1) pUS9 can complement for the loss of pUS9 in swine pathogen pseudorabies virus (PrV) (1). In contrast, varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1) pUS9 are unable to complement for a loss of pUS9 in PrV (1). In PrV (2-5), BHV-1 (6), and BHV-5 (7), pUS9 plays a major role in axonal sorting and/or anterograde axonal transport. For PrV there is also evidence for pUS9-independent anterograde axonal transport of some viral components (8, 9). In HSV-1 the contribution of pUS9 to th...

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Identification of functional marker proteins in the mammalian growth cone

Cited by 84 publications

References 44 publications

SynCAM 1 participates in axo-dendritic contact assembly and shapes neuronal growth cones

SynCAM 1 participates in axo-dendritic contact assembly and shapes neuronal growth cones

14-3-3 Proteins Regulate Protein Kinase A Activity to Modulate Growth Cone Turning Responses

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

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