PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling

Liu, Xingfeng; Huai, Jisen; Endle, Heiko; Schlüter, Leslie; Fan, Wei; Li, Yunbo; Richers, Sebastian; Yurugi, Hajime; Rajalingam, Krishnaraj; Ji, Haichao; Cheng, Hong; Rister, Benjamin; Horta, Guilherme; Baumgart, Jan; Berger, Hendrik; Laube, Gregor; Schmitt, Ulrich; Schmeißer, Michael J.; Boeckers, Tobias M.; Vlachos, Andreas; Deller, Thomas; Nitsch, Robert; Vogt, Johannes

doi:10.1016/j.devcel.2016.06.019

Cited by 37 publications

(65 citation statements)

References 57 publications

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“…Also, whether PRG3 regulates synaptic transmission as reported for PRG1 [33] needs to be further investigated. It has been reported that PRG1 affects spine density and synaptic plasticity in a cell-autonomous fashion via interacting with protein phosphatase 2A and subsequent β1-integrin activation [36]. These data have been found by investigating PRG1 deficient mice and further investigations will focus on the deletion of the prg3 gene at the genomic level to open such studies in vivo .…”

Section: Discussionmentioning

confidence: 97%

Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury

Broggini

Schnell

Ghoochani

et al. 2016

Aging

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The Plasticity Related Gene family covers five, brain-specific, transmembrane proteins (PRG1-5, also termed LPPR1-5) that operate in neuronal plasticity during development, aging and brain trauma. Here we investigated the role of the PRG family on axonal and filopodia outgrowth. Comparative analysis revealed the strongest outgrowth induced by PRG3 (LPPR1). During development, PRG3 is ubiquitously located at the tip of neuronal processes and at the plasma membrane and declines with age. In utero electroporation of PRG3 induced dendritic protrusions and accelerated spine formations in cortical pyramidal neurons. The neurite growth promoting activity of PRG3 requires RasGRF1 (RasGEF1/Cdc25) mediated downstream signaling. Moreover, in axon collapse assays, PRG3-induced neurites resisted growth inhibitors such as myelin, Nogo-A (Reticulon/RTN-4), thrombin and LPA and impeded the RhoA-Rock-PIP5K induced neurite repulsion. Transgenic adult mice with constitutive PRG3 expression displayed strong axonal sprouting distal to a spinal cord lesion. Moreover, fostered PRG3 expression promoted complex motor-behavioral recovery compared to wild type controls as revealed in the Schnell swim test (SST). Thus, PRG3 emerges as a developmental RasGRF1-dependent conductor of filopodia formation and axonal growth enhancer. PRG3-induced neurites resist brain injury-associated outgrowth inhibitors and contribute to functional recovery after spinal cord lesions. Here, we provide evidence that PRG3 operates as an essential neuronal growth promoter in the nervous system. Maintaining PRG3 expression in aging brain may turn back the developmental clock for neuronal regeneration and plasticity.

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Section: Discussionmentioning

confidence: 97%

Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury

Broggini

Schnell

Ghoochani

et al. 2016

Aging

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“…Li et al [51] recently indicated that PP2A is necessary for DS formation in striatal neurons [52]. Liu et al [53] determined that PP2A interacts with the protein PRG-1 at the postsynaptic density not only to modulate synaptic plasticity but also to produce the recruitment of focal adhesion proteins such as Src and paxillin. Here, we determined that E2 and P4 reduce PP2A activity via Src kinase, leading to an increase in WAVE1 phosphorylation and, hence, DS formation ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Rapid Estrogen and Progesterone Signaling to Dendritic Spine Formation via Cortactin/Wave1-Arp2/3 Complex

Uzair

Flamini

Sanchez³

2019

Neuroendocrinology

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Background: Synaptic plasticity is the neuronal capacity to modify the function and structure of dendritic spines (DS) in response to neuromodulators. Sex steroids, particularly 17β-estradiol (E2) and progesterone (P4), are key regulators in the control of DS formation through multiprotein complexes including WAVE1 protein, and are thus fundamental for the development of learning and memory. Objectives: The aim of this work was to evaluate the molecular switch Cdk5 kinase/protein phosphatase 2A (PP2A) in the control of WAVE1 protein (phosphorylation/dephosphorylation) and the regulation of WAVE1 and cortactin to the Arp2/3 complex, in response to rapid treatments with E2 and P4 in cortical neuronal cells. Results: Rapid treatment with E2 and P4 modified neuronal morphology and significantly increased the number of DS. This effect was reduced by the use of a Cdk5 inhibitor (Roscovitine). In contrast, inhibition of PP2A with PP2A dominant negative construct significantly increased DS formation, evidencing the participation of kinase/phosphatase in the regulation of WAVE1 in DS formation induced by E2 and P4. Cortactin regulates DS formation via Src and PAK1 kinase induced by E2 and P4. Both cortactin and WAVE1 signal to Arp2/3 complex to synergistically promote actin nucleation. Conclusion: These results suggest that E2 and P4 dynamically regulate neuron morphology through nongenomic signaling via cortactin/WAVE1-Arp2/3 complex. The control of these proteins is tightly orchestrated by phosphorylation, where kinases and phosphatases are essential for actin nucleation and, finally, DS formation. This work provides a deeper understanding of the biological actions of sex steroids in the regulation of DS turnover and neuronal plasticity processes.

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“…Integrins also cooperate with other postsynaptic regulators of spine plasticity. For instance, postsynaptic plasticity-related gene 1 (PRG-1; also known as PLPPR4), previously shown to control lysophosphatidic acid (LPA) signalling at glutamatergic synapses (Trimbuch et al, 2009), has recently been demonstrated to regulate spine density and synaptic plasticity through protein phosphatase 2A (PP2A) and β1 integrin activation (Liu et al, 2016) (Fig. 2, point 1).…”

Section: Integrins In Synaptic Plasticitymentioning

confidence: 99%

Integrin activity in neuronal connectivity

Lilja

Ivaska

2018

Journal of Cell Science

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The formation of correct synaptic structures and neuronal connections is paramount for normal brain development and a functioning adult brain. The integrin family of cell adhesion receptors and their ligands play essential roles in the control of several processes regulating neuronal connectivity - including neurite outgrowth, the formation and maintenance of synapses, and synaptic plasticity - that are affected in neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia. Many ASD- and schizophrenia-associated genes are linked to alterations in the genetic code of integrins and associated signalling pathways. In non-neuronal cells, crosstalk between integrin-mediated adhesions and the actin cytoskeleton, and the regulation of integrin activity (affinity for extracellular ligands) are widely studied in healthy and pathological settings. In contrast, the roles of integrin-linked pathways in the central nervous system remains less well defined. In this Review, we will provide an overview of the known pathways that are regulated by integrin-ECM interaction in developing neurons and in adult brain. We will also describe recent advances in the identification of mechanisms that regulate integrin activity in neurons, and highlight the interesting emerging links between integrins and neurodevelopment.

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PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling

Cited by 37 publications

References 57 publications

Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury

Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury

Rapid Estrogen and Progesterone Signaling to Dendritic Spine Formation via Cortactin/Wave1-Arp2/3 Complex

Integrin activity in neuronal connectivity

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