DAZL mediates a broad translational program regulating expansion and differentiation of spermatogonial progenitors

Abstract

Fertility across metazoa requires the germline-specific DAZ family of RNA-binding proteins. Here we examine whether DAZL directly regulates progenitor spermatogonia using a conditional genetic mouse model and in vivo biochemical approaches combined with chemical synchronization of spermatogenesis. We find that the absence of Dazl impairs both expansion and differentiation of the spermatogonial progenitor population. In undifferentiated spermatogonia, DAZL binds the 3' UTRs of ~2,500 protein-coding genes. Some targets are known regulators of spermatogonial proliferation and differentiation while others are broadly expressed, dosage-sensitive factors that control transcription and RNA metabolism. DAZL binds 3' UTR sites conserved across vertebrates at a UGUU(U/A) motif. By assessing ribosome occupancy in undifferentiated spermatogonia, we find that DAZL increases translation of its targets. In total, DAZL orchestrates a broad translational program that amplifies protein levels of key spermatogonial and gene regulatory factors to promote the expansion and differentiation of progenitor spermatogonia.

Data availability

All sequencing data generated in this study are available at NCBI Gene Expression Omnibus accession number GSE145177

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

Article and author information

Author details

  1. Maria M Mikedis

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yuting Fan

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peter K Nicholls

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5540-442X
  4. Tsutomu Endo

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Emily K Jackson

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarah A Cobb

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dirk G de Rooij

    Whitehead Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3932-4419
  8. David C Page

    Whitehead Institute, Cambridge, United States
    For correspondence
    dcpage@wi.mit.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9920-3411

Funding

Howard Hughes Medical Institute (Page laboratory)

  • David C Page

Lalor Foundation (Postdoctoral fellowship)

  • Maria M Mikedis

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD093391)

  • Maria M Mikedis

National Natural Science Foundation of China (81471507)

  • Yuting Fan

National Key Research and Development Program of China (2017YFC1001600)

  • Yuting Fan

Hope Funds for Cancer Research (HFCR-15-06-06)

  • Peter K Nicholls

National Health and Medical Research Council (GNT1053776)

  • Peter K Nicholls

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

Reviewing Editor

  1. Moira K O'Bryan, Monash University, Australia

Ethics

Animal experimentation: All experiments involving mice were performed in accordance with the guidelines of the Massachusetts Institute of Technology (MIT) Division of Comparative Medicine, which is overseen by MIT's Institutional Animal Care and Use Committee (IACUC). The animal care program at MIT/Whitehead Institute is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International (AAALAC), and meets or exceeds the standards of AAALAC as detailed in the Guide for the Care and Use of Laboratory Animals. The MIT IACUC approved this research (no. 0617-059-20).

Version history

  1. Received: March 2, 2020
  2. Accepted: July 20, 2020
  3. Accepted Manuscript published: July 20, 2020 (version 1)
  4. Version of Record published: August 24, 2020 (version 2)

Copyright

© 2020, Mikedis 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. Maria M Mikedis
  2. Yuting Fan
  3. Peter K Nicholls
  4. Tsutomu Endo
  5. Emily K Jackson
  6. Sarah A Cobb
  7. Dirk G de Rooij
  8. David C Page
(2020)
DAZL mediates a broad translational program regulating expansion and differentiation of spermatogonial progenitors
eLife 9:e56523.
https://doi.org/10.7554/eLife.56523

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https://doi.org/10.7554/eLife.56523

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