GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 signaling

Fiuza, María; Gonzàlez-Gonzàlez, Immaculada M.; Pérez‐Otaño, Isabel

doi:10.1073/pnas.1312211110

Cited by 36 publications

(40 citation statements)

References 46 publications

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“…Some examples include knockout of components of the major histocompatibility complex (MHC1), where LTD and/or ocular dominance plasticity are also impaired 94,95,113–115 , and deletion of different subunits of NMDARs, which results in increases in synapse number 93,116–119 (but see 120 ). However, whether these manipulations impact development of synapses or whether they directly prevent synapse pruning is often ambiguous 121–123 .…”

Section: Discussionmentioning

confidence: 99%

Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning

Henson

Tucker²,

Zhao

et al. 2017

Neurobiology of Learning and Memory

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Activity-dependent pruning of synaptic contacts plays a critical role in shaping neuronal circuitry in response to the environment during postnatal brain development. Although there is compelling evidence that shrinkage of dendritic spines coincides with synaptic long-term depression (LTD), and that LTD is accompanied by synapse loss, whether NMDA receptor (NMDAR)-dependent LTD is a required step in the progression toward synapse pruning is still unknown. Using repeated applications of NMDA to induce LTD in dissociated rat neuronal cultures, we found that synapse density, as measured by colocalization of fluorescent markers for pre- and postsynaptic structures, was decreased irrespective of the presynaptic marker used, post-treatment recovery time, and the dendritic location of synapses. Consistent with previous studies, we found that synapse loss could occur without apparent net spine loss or cell death. Furthermore, synapse loss was unlikely to require direct contact with microglia, as the number of these cells was minimal in our culture preparations. Supporting a model by which NMDAR-LTD is required for synapse loss, the effect of NMDA on fluorescence colocalization was prevented by phosphatase and caspase inhibitors. In addition, gene transcription and protein translation also appeared to be required for loss of putative synapses. These data support the idea that NMDAR-dependent LTD is a required step in synapse pruning and contribute to our understanding of the basic mechanisms of this developmental process.

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Section: Discussionmentioning

confidence: 99%

Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning

Henson

Tucker²,

Zhao

et al. 2017

Neurobiology of Learning and Memory

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“…Finally, although GIT and PIX are tightly associated, there are reports suggesting that GIT or PIX proteins also act independently (Loo et al, 2004;Feng et al, 2004;Fiuza et al, 2013). As most studies employ the overexpression of GIT or PIX in cells in the presence of the endogenous proteins, accurately interpreting such results can be difficult.…”

Section: Git Proteinsmentioning

confidence: 99%

“…During post-natal brain maturation in mammals, maturation of synaptic connections is marked by a transition to adult-type synaptic GluN1/GluN2 NMDA receptors from extrasynaptic NMDA receptors containing GluN3A, a subunit whose expression fades by adulthood. GluN3-containing NMDA receptors repress the formation of stable synaptic spines, in part by direct binding of the tail of GluN3A to GIT1, which prevents localization of GIT1 -β-PIX within forming spines (Fiuza et al, 2013). Intriguingly, binding of GluN3A to GIT1 reduced co-immunoprecipitation of GIT1 with β-PIX, whereas loss of GluN3A increased the association between GIT1 and β-PIX (Fiuza et al, 2013), suggesting that GluN3A binding regulates complex formation.…”

Section: Functions In the Nervous Systemmentioning

confidence: 99%

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Weiyuan

Premont

2016

Journal of Cell Science

100

130

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The GIT proteins, GIT1 and GIT2, are GTPase-activating proteins (inactivators) for the ADP-ribosylation factor (Arf ) small GTP-binding proteins, and function to limit the activity of Arf proteins. The PIX proteins, α-PIX and β-PIX (also known as ARHGEF6 and ARHGEF7, respectively), are guanine nucleotide exchange factors (activators) for the Rho family small GTP-binding protein family members Rac1 and Cdc42. Through their multi-domain structures, GIT and PIX proteins can also function as signaling scaffolds by binding to numerous protein partners. Importantly, the constitutive association of GIT and PIX proteins into oligomeric GIT-PIX complexes allows these two proteins to function together as subunits of a larger structure that coordinates two distinct small GTP-binding protein pathways and serves as multivalent scaffold for the partners of both constituent subunits. Studies have revealed the involvement of GIT and PIX proteins, and of the GIT-PIX complex, in numerous fundamental cellular processes through a wide variety of mechanisms, pathways and signaling partners. In this Commentary, we discuss recent findings in key physiological systems that exemplify current understanding of the function of this important regulatory complex. Further, we draw attention to gaps in crucial information that remain to be filled to allow a better understanding of the many roles of the GIT-PIX complex in health and disease.

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“…GIT1 can also act as a GTPase-activating protein for the ADP ribosylation factor family of small GTPases (Claing et al 2000;Vitale et al 2000), including Rac1 (Zhang et al 2005;Chang et al 2015), by binding to the C-terminal region of the Rho guanine nucleotide exchange factor 7 (ARHGEF7 or β-PIX) and promoting the interaction of β-PIX with Rac1 (Bagrodia et al 1999;Zhang et al 2005;Fiuza et al 2013). However, we observed no reproducible changes in Rac1 activity following shGit1 knockdown (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 87%

Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival

Smithson

Gutmann

2016

Genes Dev.

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As a critical regulator of cell growth, the mechanistic target of rapamycin (mTOR) protein operates as part of two molecularly and functionally distinct complexes. Herein, we demonstrate that mTOR complex molecular composition varies in different somatic tissues. In astrocytes and neural stem cells, we identified G-protein-coupled receptor kinase-interacting protein 1 (GIT1) as a novel mTOR-binding protein, creating a unique mTOR complex lacking Raptor and Rictor. Moreover, GIT1 binding to mTOR is regulated by AKT activation and is essential for mTOR-mediated astrocyte survival. Together, these data reveal that mTOR complex function is partly dictated by its molecuflar composition in different cell types.

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GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 signaling

Cited by 36 publications

References 46 publications

Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning

Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival

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