scholarly journals FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Caryn R Hale ◽  
Kirsty Sawicka ◽  
Kevin Mora ◽  
John J Fak ◽  
Jin Joo Kang ◽  
...  
Keyword(s):  
Cell Body ◽  
Pyramidal Neurons ◽  
Neuronal Cell ◽  
Alternative Polyadenylation ◽  
Cell Type ◽  
Mrna Isoforms ◽  
Protein Coding ◽  
Ca1 Pyramidal Neurons ◽  
Synaptic Functions ◽  
Cell Type Specific

Neurons rely on translation of synaptic mRNAs in order to generate activity-dependent changes in plasticity. Here we develop a strategy combining compartment-specific CLIP and TRAP in conditionally tagged mice to precisely define the ribosome-bound dendritic transcriptome of CA1 pyramidal neurons. We identify CA1 dendritic transcripts with differentially localized mRNA isoforms generated by alternative polyadenylation and alternative splicing, including many which have altered protein-coding capacity. Among dendritic mRNAs, FMRP targets were found to be overrepresented. Cell-type specific FMRP-CLIP and TRAP in microdissected CA1 neuropil revealed 383 dendritic FMRP targets and suggests that FMRP differentially regulates functionally distinct modules in CA1 dendrites and cell bodies. FMRP regulates ~15-20% of mRNAs encoding synaptic functions and 10% of chromatin modulators, in the dendrite and cell body, respectively. In the absence of FMRP, dendritic FMRP targets had increased ribosome association, consistent with a function for FMRP in synaptic translational repression. Conversely, downregulation of FMRP targets involved in chromatin regulation in cell bodies and suggest a role for FMRP in stabilizing mRNAs containing stalled ribosomes in this compartment. Together, the data support a model in which FMRP regulates the translation and expression of synaptic and nuclear proteins within different compartments of a single neuronal cell type.

scholarly journals FMRP has a cell-type-specific role in CA1 pyramidal neurons to regulate autism-related transcripts and circadian memory

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kirsty Sawicka ◽  
Caryn R Hale ◽  
Christopher Y Park ◽  
John J Fak ◽  
Jodi E Gresack ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Rna Binding ◽  
Fragile X ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Cell Type ◽  
Ca1 Pyramidal Neurons ◽  
Mrna Targets ◽  
Specific Regulation

Loss of the RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown how FMRP function varies across brain regions and cell types and how this contributes to disease pathophysiology. Here we use conditional tagging of FMRP and CLIP (FMRP cTag CLIP) to examine FMRP mRNA targets in hippocampal CA1 pyramidal neurons, a critical cell type for learning and memory relevant to FXS phenotypes. Integrating these data with analysis of ribosome-bound transcripts in these neurons revealed CA1-enriched binding of autism-relevant mRNAs, and CA1-specific regulation of transcripts encoding circadian proteins. This contrasted with different targets in cerebellar granule neurons, and was consistent with circadian defects in hippocampus-dependent memory in Fmr1 knockout mice. These findings demonstrate differential FMRP-dependent regulation of mRNAs across neuronal cell types that may contribute to phenotypes such as memory defects and sleep disturbance associated with FXS.

scholarly journals FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons

2021 ◽  
Author(s):  
Caryn R Hale ◽  
Kirsty Sawicka ◽  
Kevin Mora ◽  
John J Fak ◽  
Jin Joo Kang ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Neuronal Cell ◽  
Synaptic Proteins ◽  
Translational Repression ◽  
Functional Modules ◽  
Cell Type ◽  
Ca1 Pyramidal Neurons ◽  
Splicing Isoforms ◽  
Activity Dependent ◽  
Ribosome Association

Neurons are believed to rely on dendritic localization and translation of mRNAs in order to generate activity-dependent changes in the synaptic plasticity. Here, we develop a strategy combining compartment-specific CLIP and TRAP in conditionally tagged mice to precisely define the ribosome bound dendritic transcriptome of CA1 pyramidal neurons. This revealed transcripts that have differentially localized alternative 3′UTR and splicing isoforms. FMRP targets are overrepresented among dendritic mRNAs, and compartment-specific FMRP-CLIP defined 383 dendritic FMRP targets, and also allowed for segregation of whole-cell FMRP targets into functional modules that are locally regulated by FMRP. In the absence of FMRP, dendritic FMRP targets show increased ribosome association, consistent with reported roles for FMRP in translational repression. Together, the data support a model in which distinct patterns of FMRP localization allow it to differentially regulate the expression of nuclear proteins and synaptic proteins within different compartments of a single neuronal cell type.

scholarly journals Cell Type-Specific mRNA Dysregulation in Hippocampal CA1 Pyramidal Neurons of the Fragile X Syndrome Mouse Model

2017 ◽  
Vol 10 ◽  
Author(s):  
Laura Ceolin ◽  
Nathalie Bouquier ◽  
Jihane Vitre-Boubaker ◽  
Stéphanie Rialle ◽  
Dany Severac ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Pyramidal Neurons ◽  
Fragile X ◽  
Cell Type ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Ca1 ◽  
Cell Type Specific ◽  
Specific Mrna

scholarly journals In vivo single-cell profiling of lncRNAs during Ebola virus infection

2022 ◽  
Author(s):  
Luisa Santus ◽  
Raquel García-Pérez ◽  
Maria Sopena-Rios ◽  
Aaron E Lin ◽  
Gordon C Adams ◽  
...  
Keyword(s):  
Viral Infection ◽  
Single Cell ◽  
Ebola Virus ◽  
Cell Type ◽  
Protein Coding ◽  
Expression Variation ◽  
Lncrna Expression ◽  
Ebov Infection ◽  
Cell Type Specific

Long non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cell-type specific immune regulatory roles may differ compared to protein-coding genes. Here, we perform the first in-depth characterization of lncRNA expression variation at single-cell resolution during Ebola virus (EBOV) infection in vivo. Using bulk RNA-sequencing from 119 samples and 12 tissue types, we significantly expand the current macaque lncRNA annotation. We then profile lncRNA expression variation in immune circulating single-cells during EBOV infection and find that lncRNAs' expression in fewer cells is a major differentiating factor from their protein-coding gene counterparts. Upon EBOV infection, lncRNAs present dynamic and mostly cell-type specific changes in their expression profiles especially in monocytes, the main cell type targeted by EBOV. Such changes are associated with gene regulatory modules related to important innate immune responses such as interferon response and purine metabolism. Within infected cells, several lncRNAs have positively and negatively correlated expression with viral load, suggesting that expression of some of these lncRNAs might be directly hijacked by EBOV to attack host cells. This study provides novel insights into the roles that lncRNAs play in the host response to acute viral infection and paves the way for future lncRNA studies at single-cell resolution.

scholarly journals Target-specific M1 inputs to infragranular S1 pyramidal neurons

2016 ◽  
Vol 116 (3) ◽  
pp. 1261-1274 ◽  
Author(s):  
Amanda K. Kinnischtzke ◽  
Erika E. Fanselow ◽  
Daniel J. Simons
Keyword(s):  
Primary Motor Cortex ◽  
Pyramidal Neurons ◽  
Projection Neurons ◽  
Cell Type ◽  
Intrinsic Properties ◽  
Subcortical Structures ◽  
Medial Nucleus ◽  
Cell Type Specific ◽  
Posterior Medial Nucleus

The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237–2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.

scholarly journals Neuronal cell-type-specific alternative splicing: A mechanism for specifying connections in the brain?

Neurogenesis ◽  
2015 ◽  
Vol 2 (1) ◽  
pp. e1122699 ◽  
Author(s):  
Joshua Shing Shun Li ◽  
Grace Ji-eun Shin ◽  
S Sean Millard
Keyword(s):  
Alternative Splicing ◽  
Neuronal Cell ◽  
Cell Type ◽  
Specific Alternative ◽  
Cell Type Specific ◽  
The Brain
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