14-3-3 Proteins Regulate a Cell-Intrinsic Switch from Sonic Hedgehog-Mediated Commissural Axon Attraction to Repulsion after Midline Crossing

Yam, Patricia T.; Kent, Christopher B.; Morin, Steves; Farmer, W. Todd; Alchini, Ricardo; Lepelletier, Léa; Colman, David; Tessier‐Lavigne, Marc; Fournier, Alyson E.; Charron, Frédéric

doi:10.1016/j.neuron.2012.09.017

Cited by 94 publications

(100 citation statements)

References 34 publications

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“…While 14-3-3 proteins are known to regulate neuronal migration and axonal outgrowth (13, 26, 29, 60), their involvement in synapse formation and spine maintenance has not been fully investigated. Our study provides the first in vivo evidence of 14-3-3’s role in dendritic spine regulation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

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Qiao

Graham

et al. 2015

Biological Psychiatry

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Background The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies have suggested an association between 14-3-3 dysregulation and schizophrenia. Methods We characterized the behavioral and functional changes in the transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. Results We have recently shown that the 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. Here, we report that these 14-3-3 FKO mice display other behavioral deficits which correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. Particularly, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics due to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Conclusions Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.

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Section: Discussionmentioning

confidence: 99%

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

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Qiao

Graham

et al. 2015

Biological Psychiatry

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“…p120RasGAP Is Required for Netrin-1-dependent Attraction of Embryonic Cortical Neurons-To determine whether p120RasGAP regulates netrin-1-dependent chemoattraction, we evaluated the effect of p120RasGAP depletion on cortical growth cone turning in response to a netrin-1 gradient using a Dunn chamber turning assay (45,50,51). The growth cones of cortical neurons electroporated with control siRNA turned randomly with no particular preference for any direction when exposed to a control PBS gradient (Fig.…”

Section: Netrin-1 Promotes the Association Of P120rasgap With DCC In mentioning

confidence: 99%

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Antoine-Bertrand

Duquette

Alchini

et al. 2016

Journal of Biological Chemistry

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The receptor deleted in colorectal cancer (DCC) mediates the attraction of growing axons to netrin-1 during brain development. In response to netrin-1 stimulation, DCC becomes a signaling platform to recruit proteins that promote axon outgrowth and guidance. The Ras GTPase-activating protein (GAP) p120RasGAP inhibits Ras activity and mediates neurite retraction and growth cone collapse in response to repulsive guidance cues. Here we show an interaction between p120RasGAP and DCC that positively regulates netrin-1-mediated axon outgrowth and guidance in embryonic cortical neurons. In response to netrin-1, p120RasGAP is recruited to DCC in growth cones and forms a multiprotein complex with focal adhesion kinase and ERK. We found that Ras/ERK activities are elevated aberrantly in p120RasGAP-deficient neurons. Moreover, the expression of p120RasGAP Src homology 2 (SH2)-SH3-SH2 domains, which interact with the C-terminal tail of DCC, is sufficient to restore netrin-1-dependent axon outgrowth in p120RasGAP-deficient neurons. We provide a novel mechanism that exploits the scaffolding properties of the N terminus of p120RasGAP to tightly regulate netrin-1/DCC-dependent axon outgrowth and guidance.

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“…Endogenous Gas1 and Gnaz, and transduced Smo-GFP, are localized to enteric axonal terminals, consistent with their function at the growth cone for Shh-directed repulsion. In the CNS, Shh also acts as a chemorepulsive cue for commissural axons after midline crossing (40,41), although in that context the receptor(s) and Smo-coupled G protein(s) have yet to be identified. Our findings thus generalize the role of Shh in chemo-repulsion and extend the signaling mechanism by defining components upstream and downstream of Smo in axonal repulsion.…”

Section: Gas1-smo-gnaz Defines a Signaling Pathway For Shh-directed Ementioning

confidence: 99%

Gas1 is a receptor for sonic hedgehog to repel enteric axons

Jin

Martinelli

Zheng

et al. 2014

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

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The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Gαi proteins that can couple with Smo, G protein α Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance.enteric neuron | axon guidance | chemorepellent | Hedgehog | Gas1

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14-3-3 Proteins Regulate a Cell-Intrinsic Switch from Sonic Hedgehog-Mediated Commissural Axon Attraction to Repulsion after Midline Crossing

Cited by 94 publications

References 34 publications

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Gas1 is a receptor for sonic hedgehog to repel enteric axons

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