FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons
- Rockefeller University, United States
Abstract
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE174303, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174303, token: qbqdiogwzxuflob
-
Cell-type and compartment-specific TRAP-seq, RNAseq, FMRP-CLIP, and PAPERCLIP from mouse microdissected CA1.NCBI Gene Expression Omnibus, GSE174303.
Article and author information
Author details
Funding
Leon Levy Foundation
- Caryn R Hale
Simons Foundation
- Caryn R Hale
- Kirsty Sawicka
- Kevin Mora
- John J Fak
- Jin Joo Kang
- Paula Cutrim
- Robert B Darnell
National Institute of General Medical Sciences (R35NS097404)
- Caryn R Hale
- Kirsty Sawicka
- Kevin Mora
- John J Fak
- Jin Joo Kang
- Paula Cutrim
- Robert B Darnell
Howard Hughes Medical Institute
- Robert B Darnell
National Institutes of Health (NS081706)
- Caryn R Hale
- Kirsty Sawicka
- Kevin Mora
- John J Fak
- Jin Joo Kang
- Paula Cutrim
- Robert B Darnell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse procedures were conducted according to the Institutional Animal Care and Use Committee (IACUC) guidelines at the Rockefeller University using protocol numbers 14678, 17013 and 20028.
Copyright
© 2021, Hale et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,523
- views
-
- 624
- downloads
-
- 37
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons
eLife 10:e71892.
https://doi.org/10.7554/eLife.71892
Further reading
-
- Cancer Biology
- Genetics and Genomics
Solitary fibrous tumors have gene expression signatures similar to those of neuroendocrine tumors.
-
- Genetics and Genomics
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
