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

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

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Caryn R Hale

    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
    For correspondence
    chale@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Kirsty Sawicka

    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4195-6327
  3. Kevin Mora

    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. John J Fak

    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jin Joo Kang

    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Paula Cutrim

    Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Katarzyna Cialowicz

    Bio-Imaging Resource Center, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Thomas S Carroll

    Bioinformatics Resouce Center, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Robert B Darnell

    Howard Hughes Medical Institute, Rockefeller University, New York, United States
    For correspondence
    darnelr@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5134-8088

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.

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  1. Caryn R Hale
  2. Kirsty Sawicka
  3. Kevin Mora
  4. John J Fak
  5. Jin Joo Kang
  6. Paula Cutrim
  7. Katarzyna Cialowicz
  8. Thomas S Carroll
  9. Robert B Darnell
(2021)
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

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https://doi.org/10.7554/eLife.71892

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