Neurons are among the most compartmentalized and interactive of all cell types. Like all cells, neurons use proteins as the main sensors and effectors. The modification of the proteome in axons and ...dendrites is used to guide the formation of synaptic connections and to store information. In this Review, we discuss the data indicating that an important source of protein for dendrites, axons and their associated elements is provided by the local synthesis of proteins. We review the data indicating the presence of the machinery required for protein synthesis, the direct visualization and demonstration of protein synthesis, and the established functional roles for local translation for many different neuronal functions. Finally, we consider the open questions and future directions in this field.
Long-lasting changes in synaptic efficacy, such as those underlying long-term memory, require transcription. Activity-dependent transport of synaptically localized transcriptional regulators ...provides a direct means of coupling synaptic stimulation with changes in transcription. The CREB-regulated transcriptional coactivator (CRTC1), which is required for long-term hippocampal plasticity, binds CREB to potently promote transcription. We show that CRTC1 localizes to synapses in silenced hippocampal neurons but translocates to the nucleus in response to localized synaptic stimulation. Regulated nuclear translocation occurs only in excitatory neurons and requires calcium influx and calcineurin activation. CRTC1 is controlled in a dual fashion with activity regulating CRTC1 nuclear translocation and cAMP modulating its persistence in the nucleus. Neuronal activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of stimuli to specific changes in gene expression. Together, our results indicate that synapse-to-nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity.
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► CRTC1 undergoes calcium-dependent nuclear transport from stimulated synapses ► cAMP increases the persistence of nuclear CRTC1, not its initial translocation ► Neuronal activity induces complex changes in CRTC1 phosphorylation ► CRTC1 is required for stimulus-induced activation of select CREB targets
How do calcium and cAMP differentially influence the dynamic gene expression required for neuronal plasticity and long-term memory formation? Local synaptic activity triggers calcium-dependent nuclear transport of CRCT1, whereas cAMP regulates CRCT1's nuclear persistence, suggesting that this transcriptional coactivator integrates both synaptic and neuromodulatory stimuli.
The localization of mRNAs to subcellular compartments provides a mechanism for regulating gene expression with exquisite temporal and spatial control. Recent studies suggest that a large fraction of ...mRNAs localize to distinct cytoplasmic domains. In this Review, we focus on
cis-acting RNA localization elements, RNA-binding proteins, and the assembly of mRNAs into granules that are transported by molecular motors along cytoskeletal elements to their final destination in the cell.
Bicyclic nitroxyl derivatives, such as 2-azaadamantane N-oxyl (AZADO) and 9-azabicyclo3.3.1nonane N-oxyl (ABNO), have emerged as highly effective alternatives to TEMPO-based catalysts for ...selective oxidation reactions (TEMPO = 2,2,6,6-tetramethyl-1-piperidine N-oxyl). Their efficacy is widely attributed to their smaller steric profile; however, electrocatalysis studies described herein show that the catalytic activity of nitroxyls is more strongly affected by the nitroxyl/oxoammonium redox potential than by steric effects. The inexpensive, high-potential TEMPO derivative, 4-acetamido-TEMPO (ACT), exhibits higher electrocatalytic activity than AZADO and ABNO for the oxidation of primary and secondary alcohols. Mechanistic studies provide insights into the origin of these unexpected reactivity trends. The superior activity of ACT is especially noteworthy at high pH, where bicyclic nitroxyls are inhibited by formation of an oxoammonium hydroxide adduct.
As the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing and the surviving population is aging, it is necessary to identify cancer patients who ...are at an increased risk of death from heart disease. The purpose of this study is to identify cancer patients at highest risk of fatal heart disease compared to the general population and other cancer patients at risk of death during the study time period. Here we report that 394,849 of the 7,529,481 cancer patients studied died of heart disease. The heart disease-specific mortality rate is 10.61/10,000-person years, and the standardized mortality ratio (SMR) of fatal heart disease is 2.24 (95% CI: 2.23-2.25). Compared to other cancer patients, patients who are older, male, African American, and unmarried are at a greatest risk of fatal heart disease. For almost all cancer survivors, the risk of fatal heart disease increases with time.
Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is ...also alternatively spliced to produce cytoplasmic isoforms. To investigate the function of cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that Rbfox1 bound predominantly to introns in nascent RNA, while cytoplasmic Rbox1 bound to 3ʹ UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and Rbfox1 and miRNA binding sites overlapped significantly. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease.
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•Nuclear and cytoplasmic Rbfox1 isoforms regulate distinct neuronal mRNAs•Cytoplasmic Rbfox1 regulates the stability and translation of its target mRNAs•Rbfox1 and miRNA binding sites overlap significantly in target mRNA 3′ UTRs•Cytoplasmic Rbfox1 targets are enriched in cortical development and autism genes
Rbfox1 regulates the splicing of many exons in the nucleus of neurons. Lee at al. demonstrate that Rbfox1 also binds to the 3ʹ UTR of target mRNAs in the cytoplasm to upregulate the expression of synaptic and autism-related genes.
A simple cobalt(ii)/
-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding ...(hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (
) under process-relevant reaction conditions.
The Cell Biology of Synaptic Plasticity Ho, Victoria M.; Lee, Ji-Ann; Martin, Kelsey C.
Science (American Association for the Advancement of Science),
11/2011, Letnik:
334, Številka:
6056
Journal Article
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Synaptic plasticity is the experience-dependent change in connectivity between neurons that is believed to underlie learning and memory. Here, we discuss the cellular and molecular processes that are ...altered when a neuron responds to external stimuli, and how these alterations lead to an increase or decrease in synaptic connectivity. Modification of synaptic components and changes in gene expression are necessary for many forms of plasticity. We focus on excitatory neurons in the mammalian hippocampus, one of the best-studied model systems of learning-related plasticity.
An accurate diagnostic test is an essential aspect of successfully monitoring and managing wildlife diseases. Lymphoproliferative Disease Virus (LPDV) is an avian retrovirus that was first identified ...in domestic turkeys in Europe and was first reported in a Wild Turkey (Meleagris gallopavo) in the United States in 2009. It has since been found to be widely distributed throughout North America. The majority of studies have utilized bone marrow and PCR primers targeting a 413-nucleotide sequence of the gag gene of the provirus to detect infection. While prior studies have evaluated the viability of other tissues for LPDV detection (whole blood, spleen, liver, cloacal swabs) none to date have studied differences in detection rates when utilizing different genomic regions of the provirus. This study examined the effectiveness of another section of the provirus, a 335-nucleotide sequence starting in the U3 region of the LTR (Long Terminal Repeat) and extending into the Matrix of the gag region (henceforth LTR), for detecting LPDV. Bone marrow samples from hunter-harvested Wild Turkeys (n = 925) were tested for LPDV with the gag gene and a subset (n = 417) including both those testing positive and those where LPDV was not detected was re-tested with LTR. The positive percent agreement (PPA) was 97.1% (68 of 70 gag positive samples tested positive with LTR) while the negative percent agreement (NPA) was only 68.0% (236 of 347 gag negative samples tested negative with LTR). Cohen's Kappa (κ = 0.402, Z = 10.26, p<0.0001) and the McNemar test (OR = 55.5, p<0.0001) indicated weak agreement between the two gene regions. We found that in Iowa Wild Turkeys use of the LTR region identified LPDV in many samples in which we failed to detect LPDV using the gag region and that LTR may be more appropriate for LPDV surveillance and monitoring. However, neither region of the provirus resulted in perfect detection and additional work is necessary to determine if LTR is more reliable in other geographic regions where LPDV occurs.
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