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.

Reviewing Editor

  1. Robert H Singer, Albert Einstein College of Medicine, United States

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.

Version history

  1. Received: July 2, 2021
  2. Preprint posted: July 19, 2021 (view preprint)
  3. Accepted: December 13, 2021
  4. Accepted Manuscript published: December 23, 2021 (version 1)
  5. Version of Record published: February 7, 2022 (version 2)

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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