Purinergic receptor P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, Schwann cell proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis

  1. Jennifer Patritti Cram
  2. Jianqiang Wu
  3. Robert A Coover
  4. Tilat A Rizvi
  5. Katherine E Chaney
  6. Ramya Ravindran
  7. Jose A Cancelas
  8. Robert J Spinner
  9. Nancy Ratner  Is a corresponding author
  1. University of Cincinnati, United States
  2. Cincinnati Children's Hospital Medical Center, United States
  3. High Point University, United States
  4. Mayo Clinic, United States

Abstract

Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2RY14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs and mouse SCPs. Mouse Nf1-/-SCP self-renewal was reduced by genetic or pharmacological inhibition of P2RY14. In a mouse model of NF1, genetic deletion of P2RY14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2RY14 signals via Gi to increase intracellular cAMP, implicating P2RY14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2RY14 inhibitor diminished NF1-/-SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identifyP2RY14 as a critical regulator of SCP self-renewal, SC proliferation and neurofibroma initiation.

Data availability

The data sets and original figures generated during this study will be available at Synapse Project (https://www.synapse.org/).

The following data sets were generated

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Author details

  1. Jennifer Patritti Cram

    Neuroscience Graduate Program, University of Cincinnati, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5971-0849
  2. Jianqiang Wu

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Robert A Coover

    Department of Basic Pharmaceutical Sciences, High Point University, High Point, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tilat A Rizvi

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine E Chaney

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ramya Ravindran

    Molecular and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jose A Cancelas

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Robert J Spinner

    Department of Neurosurgery, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nancy Ratner

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    nancy.ratner@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5030-9354

Funding

National Institutes of Health (T32-NS007453)

  • Jennifer Patritti Cram

Children's Tumor Foundation Younf Investigator Award

  • Jennifer Patritti Cram

National Institutes of Health (NIH-R01-NS28840)

  • Nancy Ratner

National Institutes of Health (NIH-R37-NS083580)

  • Nancy Ratner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. William C Hahn, Dana-Farber Cancer Institute, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2018-0103 expiration 01-2022) of Cincinnati Children's Hospital. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Cincinnati Children's Hospital.

Version history

  1. Received: September 1, 2021
  2. Preprint posted: September 24, 2021 (view preprint)
  3. Accepted: January 19, 2022
  4. Accepted Manuscript published: March 21, 2022 (version 1)
  5. Version of Record published: March 28, 2022 (version 2)

Copyright

© 2022, Patritti Cram 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. Jennifer Patritti Cram
  2. Jianqiang Wu
  3. Robert A Coover
  4. Tilat A Rizvi
  5. Katherine E Chaney
  6. Ramya Ravindran
  7. Jose A Cancelas
  8. Robert J Spinner
  9. Nancy Ratner
(2022)
Purinergic receptor P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, Schwann cell proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
eLife 11:e73511.
https://doi.org/10.7554/eLife.73511

Share this article

https://doi.org/10.7554/eLife.73511

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