Polypyrimidine tract binding proteins are essential for B cell development

  1. Elisa Monzón-Casanova  Is a corresponding author
  2. Louise S Matheson
  3. Kristina Tabbada
  4. Kathi Zarnack
  5. Christopher WJ Smith
  6. Martin Turner  Is a corresponding author
  1. The Babraham Institute, United Kingdom
  2. Goethe University Frankfurt, Germany
  3. University of Cambridge, United Kingdom

Abstract

Polypyrimidine Tract Binding Protein 1 (PTBP1) is a RNA-binding protein (RBP) expressed throughout B cell development. Deletion of Ptbp1 in mouse pro-B cells results in upregulation of PTBP2 and normal B cell development. We show that PTBP2 compensates for PTBP1 in B cell ontogeny as deletion of both Ptbp1 and Ptbp2 results in a complete block at the pro-B cell stage and a lack of mature B cells. In pro-B cells PTBP1 ensures precise synchronisation of the activity of cyclin dependent kinases at distinct stages of the cell cycle, suppresses S-phase entry and promotes progression into mitosis. PTBP1 controls mRNA abundance and alternative splicing of important cell cycle regulators including CYCLIN-D2, c-MYC, p107 and CDC25B. Our results reveal a previously unrecognised mechanism mediated by a RBP that is essential for B cell ontogeny and integrates transcriptional and post-translational determinants of progression through the cell cycle.

Data availability

mRNAseq libraries and iCLIP analysis generated in this study have been deposited in GEO and can be accessed with the GSE136882 accession code at GEO. Mitogen-activated primary B cell mRNAseq libraries were previously reported and can be accessed with the GSM1520115, GSM1520116, GSM1520117and GSM1520118 accession codes in GEO.

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

Article and author information

Author details

  1. Elisa Monzón-Casanova

    Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom
    For correspondence
    elisa.monzon-casanova@babraham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Louise S Matheson

    Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Kristina Tabbada

    Next Generation Sequencing Facility, The Babraham Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Kathi Zarnack

    Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3527-3378
  5. Christopher WJ Smith

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2753-3398
  6. Martin Turner

    Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom
    For correspondence
    martin.turner@babraham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3801-9896

Funding

Biotechnology and Biological Sciences Research Council (BB/J00152X/1)

  • Martin Turner

Biotechnology and Biological Sciences Research Council (BB/P01898X/1)

  • Elisa Monzón-Casanova
  • Martin Turner

Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0407)

  • Martin Turner

Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0427)

  • Martin Turner

Wellcome (200823/Z/16/Z)

  • Martin Turner

European Cooperation in Science and Technology (CA17103)

  • Elisa Monzón-Casanova

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

Ethics

Animal experimentation: Mice were bred and maintained in the Babraham Institute Biological Support Unit. Since the opening of this barrier facility (2009), no primary pathogens or additional agents listed in the FELASA recommendations have been confirmed during health monitoring surveys of the stock holding rooms. Ambient temperature was ~19-21{degree sign}C and relative humidity 52%. Lighting was provided on a 12-hour light: 12-hour dark cycle including 15 min 'dawn' and 'dusk' periods of subdued lighting. After weaning, mice were transferred to individually ventilated cages with 1-5 mice per cage. Mice were fed CRM (P) VP diet (Special Diet Services) ad libitum and received seeds (e.g. sunflower, millet) at the time of cage-cleaning as part of their environmental enrichment. All mouse experimentation was approved by the Babraham Institute Animal Welfare and Ethical Review Body (UK Home Office Project Licence /P4D4AF812). Animal husbandry and experimentation complied with existing European Union and United Kingdom Home Office legislation and local standards.

Reviewing Editor

  1. Douglas L Black, University of California, Los Angeles, United States

Version history

  1. Received: November 13, 2019
  2. Accepted: February 20, 2020
  3. Accepted Manuscript published: February 21, 2020 (version 1)
  4. Version of Record published: March 5, 2020 (version 2)

Copyright

© 2020, Monzón-Casanova 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. Elisa Monzón-Casanova
  2. Louise S Matheson
  3. Kristina Tabbada
  4. Kathi Zarnack
  5. Christopher WJ Smith
  6. Martin Turner
(2020)
Polypyrimidine tract binding proteins are essential for B cell development
eLife 9:e53557.
https://doi.org/10.7554/eLife.53557

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