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Pumilio2 and Staufen2 selectively balance the synaptic proteome

ABSTRACT: Cells, in particular neurons, have the capacity to adapt to environmental stimuli, a phenomenon termed cellular plasticity. The underlying processes are controlled by a network of RNA-binding proteins (RBPs). Their impact on cellular plasticity, however, is largely unknown. To address this important question, we chose Pumilio2 (Pum2) and Staufen2 (Stau2) that both regulate synaptic transmission. Surprisingly, even though both RBPs dynamically interact with each other in neurons, their respective impact on the transcriptome and proteome is highly selective. While Pum2 deficiency leads to reduced translation and protein expression, Stau2 depletion preferentially impacts RNA levels and increases protein abundance. Furthermore, we show that Pum2 activates expression of key GABAergic synaptic components, e.g. the GABAA receptor scaffold protein Gephyrin. Consequently, Pum2 depletion selectively reduced the amplitude of miniature inhibitory postsynaptic currents. Together, our data clearly demonstrate that RBPs are needed to maintain proteostasis in order to control distinct signaling pathways which critically balance synaptic transmission.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE173596 | GEO | 2021/04/30

REPOSITORIES: GEO

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Pumilio2 and Staufen2 selectively balance the synaptic proteome

Project description:Cells, in particular neurons, have the capacity to adapt to environmental stimuli, a phenomenon termed cellular plasticity. The underlying processes are controlled by a network of RNA-binding proteins (RBPs). Their impact on cellular plasticity, however, is largely unknown. To address this important question, we chose Pumilio2 (Pum2) and Staufen2 (Stau2) that both regulate synaptic transmission. Importantly, even though both RBPs dynamically interact with each other in neurons, their respective impact on the transcriptome and proteome is highly selective. While Pum2 deficiency leads to reduced translation and protein expression, Stau2 depletion preferentially impacts RNA levels and increases protein abundance. Furthermore, Pum2 activates expression of key GABAergic synaptic components, e.g. the GABAA receptor scaffold protein Gephyrin. Consequently, Pum2 depletion selectively reduced the amplitude of miniature inhibitory postsynaptic currents. Together, our data demonstrate that RBPs are needed to maintain proteostasis in order to control distinct signaling pathways which critically balance synaptic transmission.

2021-06-23 | PXD025738 | Pride

IP Staufen2

Project description:In human cells, Staufen2 is a double-stranded RNA-binding protein involved in several cellular functions. Although 51% identical to Staufen1, these proteins are nevertheless found in different RNA particles. In addition, differential splicing events generate Staufen2 isoforms that only differ at their N-terminal extremities. We used a genome wide approach to identify and compare the mRNA targets of mammalian Staufen2 isoforms. The mRNA content of Staufen mRNPs was identified by probing DNA microarrays with probes derived from mRNAs isolated from immunopurified Staufen2-containing complexes following transfection of HEK293T cells with Stau2-HA (59kDa) or Stau2-HA (62kDa) expressors. Our results indicate that 11% of the cellular RNAs expressed in HEK293T cells are found in Stau2-containing mRNPs. There is a predominance of mRNAs involved in cell metabolism, transport, transcription, regulation of cell processes and catalytic activity. Keywords: Immunoprecipitation, Staufen, microarray

2008-01-18 | GSE8437 | GEO

Pumilio2 and Staufen2 selectively balance the synaptic proteome

Project description:Pumilio2 and Staufen2 selectively balance the synaptic proteome

| PRJNA726236 | ENA

Chromatin immunoprecipitation profiling of human HEK293 cells transiantly transfected with plasmids coding for Staufen2-HA isoforms

2008-06-16 | E-GEOD-8437 | biostudies-arrayexpress

An In Vivo Genome-Wide CRISPR Screen Identifies the RNA-Binding Protein Staufen2 as a Key Regulator of Myeloid Leukemia

Project description:While Chronic Myelogenous Leukemia (CML) is generally well controlled with Imatinib and other kinase inhibitors, blast crisis CML (bcCML) continues to be resistant to current therapies and remains highly lethal. In this study, we identify the double stranded RNA binding protein Stau2 as a as key new dependency of bcCML. To define the impact of Staufen2 in myeloid leukemia, we developed a germline knockout with targeted loss of its RNA binding domains. Genetic deletion of Staufen2 led to a profound decrease in bcCML growth and propagation, and markedly improved overall survival in mouse models. Further, Staufen2 was also expressed and required for growth of primary bcCML as well as de novo AML patient samples, indicating a conserved utilization across human disease. Finally, an integrated computational analysis of eCLIP, RNA-Seq analysis and the functional genomic CRISPR screen identified Staufen2 as a regulator of a remarkable network of broad acting chromatin modifiers, resulting in changes in global histone methylation patterns.

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Stau2 RIP-Chip in Mouse E13-14 Cortex

Project description:The double-stranded RNA binding protein Staufen2 (Stau2) is asymmetrically localized and segregated during asymmetric cell divisions in the developing mouse cortex and promotes intermediate progenitor cell fate. We carry out RNA immunoprecipitation with a Stau2 specific antibody, followed by microarray analysis to identify Stau2 assoicated RNAs that may be shuttled asymmetrically into one daughter cell thus affecting cell fate. Cortex was dissected from E13-14 timed-pregnant Swiss Webster Mice (Taconic) and RNA immunoprecipitation followed by microarray analysis was carried out to identy Stau2 associated RNA cargos.

2012-12-21 | E-GEOD-38222 | biostudies-arrayexpress

Composition of Staufen2 ribonucleoprotein particles in neurons

Project description:In neurons, many mRNAs are transported along neuronal dendrites to their site of translation by ribonucleoprotein complexes (mRNPs). Numerous mRNA-binding, motor and regulatory proteins within mRNPs finely regulate the fate of each of these mRNAs and their specific combination is likely to define different types of mRNA complexes and their neuronal functions. Staufen2 is a well known mRNA-binding protein present in distinct population of mRNPs in neurons and is implicated in the transport of mRNAs along the dendritic microtubules. However, little is known about the associated mRNAs in Staufen2 neuronal mRNPs complexes. As a means to understand its role in neuronal processes, a genome wide approach has been used to identify mRNAs that are co-immunoprecipitated with Staufen2 complexes from embryonic rat brains. The genome wide approach identified 1780 mRNAs associated with Staufen2 mRNPs that code for proteins involved in cellular processes such as post-translational protein modifications, RNA metabolism, intracellular transport and translation. All these mRNAs are consistent with the role of Staufen2 in synaptogenesis.

2010-07-06 | GSE16437 | GEO

Stau2 RIP-Chip in Mouse E13-14 Cortex

2012-12-21 | GSE38222 | GEO

The dsRBP Staufen2 governs RNP assembly of neuronal Argonaute proteins

Project description:Here, we have characterized the role of the RNA-binding protein Staufen2, a potential Ago interactor, in RNP assembly. Staufen2 depletion resulted in the upregulation of Ago1/2 and the RISC effector proteins Ddx6 and Dcp1a. This upregulation was accompanied by the displacement of Ago2 from processing bodies, large RNPs implicated in RNA storage, and subsequent association of Ago2 with translating polysomes. Analysis of miRNA expression levels did not reveal changes of global miRNA abundance. In parallel, Staufen2 deficiency yielded decreased global translation. As the observed phenotype can be rescued by Ago1/2 knockdown, we propose a working model in which both Staufen2 and Ago proteins critically depend on each other and contribute to neuronal homeostasis.

2022-05-31 | GSE185935 | GEO

Altered Glutamate Receptor Ionotropic Delta Subunit 2 expression in Stau2 deficient cerebellar Purkinje cells in the adult brain

Project description:Staufen2 (Stau2) is an RNA-binding protein that is involved in dendritic spine morphogenesis and function. Several studies have recently investigated the role of Stau2 in the regulation of its neuronal target mRNAs, with particular focus on the hippocampus. Here, we provide evidence for Stau2 expression and function in cerebellar Purkinje cells. We show that Stau2 downregulation (Stau2GT) lead to an increase of the glutamate receptor ionotropic delta subunit 2 (GluD2) in Purkinje cells when animals performed physical activity by voluntary wheel running. Furthermore, Stau2GT mice showed lower performance in motor coordination assays but enhanced motor learning abilities, concomitantly with an increase in dendritic GluD2 expression. Together, our results suggest a novel role of Stau2 in Purkinje cell synaptogenesis in the mouse cerebellum

2019-04-23 | GSE126996 | GEO

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