Nogo and Nogo receptor: Relevance to schizophrenia?

Willi, Roman

doi:10.1016/j.nbd.2013.01.011

Cited by 42 publications

(41 citation statements)

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“…Recent evidence suggests that aberrant Nogo-A signaling poses an increased risk for schizophrenia (detailed review in ref. 24). We applied a Pol IIdriven miRNA expression strategy for RNAi-mediated mRNA knockdown in transgenic rats, resulting in an ∼50% reduction of neuronal Nogo-A protein in different regions of the CNS.…”

Section: Discussionmentioning

confidence: 99%

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function

Tews

Shi

Arzt

et al. 2013

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

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We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a micro-RNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in longterm potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient micro-RNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.animal model | Rtn4 | learning | memory G ene knockout (KO) technology has spurred the analysis of gene functions in mice during the past two decades (1) and has recently been expanded to other species using new genome modification technologies (2). Although germ-line gene ablation is a very powerful tool for investigating gene function in vivo, its most important drawback is that the complete loss of gene function often leads to molecular compensation, obscuring the role of the deleted gene. Tissue-or cell-specific KOs are more specific but are currently confined to mice as a model system. RNA interference (RNAi) is a viable alternative to the KO approach and represents a fast and powerful tool for manipulating gene expression (3). RNAi technology not only allows keeping the endogenous genomic locus intact, but it also enables the knockdown of multiple genes at the same time or the selective depletion of a specific isoform of mRNA transcripts (4). Another advantage is offered by the possibility of creating hypomorphic alleles instead of complete KOs, which can avoid embryonic lethality and better mirrors many human diseases and therapeutic interventions.Elucidating gene functions in transgenic rats has several important advantages over using mice (5). Their larger size simplifies interventions, such as microsurgery and multiple site in vivo electrophysiological recordings (6). Furthermore, higher-order cognitive functions are more developed in this social rodent species than in the more solitarily living mice (7,8). Hence, many behavioral tests are more advanced or validated for the rat species, especially regarding the behavioral assessment of complex neuropsychiatric disease phenotypes, such as negative symptoms in schizophrenia.For the rat, only polymerase (Pol) III-controlled shRNA RNAi models have been cre...

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Section: Discussionmentioning

confidence: 99%

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function

Tews

Shi

Arzt

et al. 2013

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

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“…Rtn4 is of particular interest because it is primarily responsible for generating or stabilizing the tubular ER in mammalian cells. Rtn4 is critical in neuronal cell processes because it inhibits spontaneous neurite outgrowth (14) and restricts neuronal plasticity (15), and it has been implicated in several neural diseases, including schizophrenia and motor neuron disease (16)(17)(18).…”

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confidence: 99%

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

Brady

Claridge

Smith

et al. 2015

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

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The integral membrane proteins of the DP1 (deleted in polyposis) and reticulon families are responsible for maintaining the high membrane curvature required for both smooth endoplasmic reticulum (ER) tubules and the edges of ER sheets, and mutations in these proteins lead to motor neuron diseases, such as hereditary spastic paraplegia. Reticulon/DP1 proteins contain reticulon homology domains (RHDs) that have unusually long hydrophobic segments and are proposed to adopt intramembrane helical hairpins that stabilize membrane curvature. We have characterized the secondary structure and dynamics of the DP1 family protein produced from the YOP1 gene (Yop1p) and identified a C-terminal conserved amphipathic helix (APH) that, on its own, interacts strongly with negatively charged membranes and is necessary for membrane tubule formation. Analyses of DP1 and reticulon family members indicate that most, if not all, contain C-terminal sequences capable of forming APHs. Together, these results indicate that APHs play a previously unrecognized role in RHD membrane curvature stabilization.T he endoplasmic reticulum (ER) is the largest membranebound organelle in the eukaryotic cell and adopts diverse morphologies, including tubules that extend outward to the cell periphery and sheet-like structures closer to the nucleus (1, 2). The regions of high membrane curvature that are found in the ER tubules and sheets are stabilized by the DP1 (deleted in polyposis) and reticulon classes of integral membrane proteins (3-5). Consistent with their role in ER morphology, similar proteins have not been found in prokaryotes (6).There are six human DP1 proteins originally identified as accessory proteins facilitating the expression of odorant receptors, and thus termed receptor expression-enhancing proteins (REEPs) (7). The ability of REEPs to facilitate receptor trafficking has recently been related back to their ER shaping activities (8). The importance of REEPs in ER morphology is also highlighted by their implication in human diseases that are associated with neurons having long axons and requiring an extended tubular ER (9, 10). For example, mutations in the transmembrane domain of REEP1, which is primarily expressed in neurons (11), lead to pure forms of hereditary spastic paraplegia (HSP) (12, 13).The reticulon family in humans comprises four members, Rtn1-Rtn4 (6). Rtn4 is of particular interest because it is primarily responsible for generating or stabilizing the tubular ER in mammalian cells. Rtn4 is critical in neuronal cell processes because it inhibits spontaneous neurite outgrowth (14) and restricts neuronal plasticity (15), and it has been implicated in several neural diseases, including schizophrenia and motor neuron disease (16-18).The DP1 and reticulon proteins have in common a region containing two, unusually long hydrophobic segments (≈35 aa in length each) known as a reticulon homology domain (RHD) (6). In humans, REEPs 1-6 are similar overall; however, the RHD of REEPs 1-4 is truncated (Fig. S1). REEPs 1-4 also possess...

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“…It is believed that neuronally differentiated P19 cells provide a good in vitro experimental model to study the presence and role of these Nogo binding partners and signaling molecules activated by Nogo-66. Recently, Nogo and NgR1 are also being studied for their possible involvement in CNS disorders or diseases, such as Alzheimer's disease, schizophrenia and multiple sclerosis [27,28,29]. We also believe that this P19 cell model could be an efficient tool to elucidate whether signaling events of Nogo and NgR1 interact with each other to perform any physiological functions, such as LTP or LTD (long-term depression) or participate in pathologic conditions of the CNS mentioned above.…”

Section: Discussionmentioning

confidence: 99%

NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

Lee

Yun

Baek

et al. 2015

Korean J Physiol Pharmacol

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NgR1, a Nogo receptor, is involved in inhibition of neurite outgrowth and axonal regeneration and regulation of synaptic plasticity. P19 embryonal carcinoma cells were induced to differentiate into neuron-like cells using all trans-retinoic acid and the presence and/or function of cellular molecules, such as NgR1, NMDA receptors and STAT3, were examined. Neuronally differentiated P19 cells expressed the mRNA and protein of NgR1, which could stimulate the phosphorylation of STAT3 when activated by Nogo-P4 peptide, an active segment of Nogo-66. During the whole period of differentiation, mRNAs of all of the NMDA receptor subtypes tested (NR1, NR2A-2D) were consistently expressed, which meant that neuronally differentiated P19 cells maintained some characteristics of neurons, especially central nervous system neurons. Our results suggests that neuronally differentiated P19 cells expressing NgR1 may be an efficient and convenient in vitro model for studying the molecular mechanism of cellular events that involve NgR1 and its binding partners, and for screening compounds that activate or inhibit NgR1.

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Nogo and Nogo receptor: Relevance to schizophrenia?

Cited by 42 publications

References 100 publications

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

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