Nucleoporin107 mediates female sexual differentiation via Dsx

  1. Tikva Shore
  2. Tgst Levi
  3. Rachel Kalifa
  4. Amatzia Dreifuss
  5. Dina Rekler
  6. Ariella Weinberg-Shukron
  7. Yuval Nevo
  8. Tzofia Bialistoky
  9. Victoria Moyal
  10. Merav Yaffa Gold
  11. Shira Leebhoff
  12. David Zangen
  13. Girish Deshpande  Is a corresponding author
  14. Offer Gerlitz  Is a corresponding author
  1. The Hebrew University, Israel
  2. Hebrew University Hadassah Medical School, Israel
  3. The Hadassah Hebrew University Medical Center, Israel
  4. Hadassah Hebrew University Medical Center, Israel
  5. Princeton University, United States

Abstract

We recently identified a missense mutation in Nucleoporin107 (Nup107; D447N) underlying XX-ovarian-dysgenesis, a rare disorder characterized by underdeveloped and dysfunctional ovaries. Modeling of the human mutation in Drosophila or specific knockdown of Nup107 in the gonadal soma resulted in ovarian-dysgenesis-like phenotypes. Transcriptomic analysis identified the somatic sex-determination gene doublesex (dsx) as a target of Nup107. Establishing Dsx as a primary relevant target of Nup107, either loss or gain of Dsx in the gonadal soma is sufficient to mimic or rescue the phenotypes induced by Nup107 loss. Importantly, the aberrant phenotypes induced by compromising either Nup107 or dsx are reminiscent of BMP signaling hyperactivation. Remarkably, in this context, the metalloprotease AdamTS-A, a transcriptional target of both Dsx and Nup107, is necessary for the calibration of BMP signaling. As modulation of BMP signaling is a conserved critical determinant of soma-germline interaction, the sex and tissue specific deployment of Dsx-F by Nup107 seems crucial for the maintenance of the homeostatic balance between the germ cells and somatic gonadal cells.

Data availability

All raw RNA-seq data, as well as software versions and parameters, have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE141094

The following data sets were generated

Article and author information

Author details

  1. Tikva Shore

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7140-0226
  2. Tgst Levi

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9221-1873
  3. Rachel Kalifa

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Amatzia Dreifuss

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Dina Rekler

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Ariella Weinberg-Shukron

    Medical Genetics Institute, Hebrew University Hadassah Medical School, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuval Nevo

    Bioinformatics Unit of the I-CORE Computation Center, The Hadassah Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Tzofia Bialistoky

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Victoria Moyal

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Merav Yaffa Gold

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9978-2262
  11. Shira Leebhoff

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. David Zangen

    Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Girish Deshpande

    Department of Molecular Biology, Princeton University, Princeton, United States
    For correspondence
    gdeshpande@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. Offer Gerlitz

    Department of Developmental Biology and Cancer Research, The Hebrew University, Jerusalem, Israel
    For correspondence
    offerg@ekmd.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1574-2088

Funding

Israel Science Foundation (1788/15)

  • David Zangen
  • Offer Gerlitz

Israel Science Foundation (1814/19-)

  • David Zangen
  • Offer Gerlitz

National Institute of Health (093913)

  • Girish Deshpande

Ministry of Science and Technology

  • Tgst Levi

Ministry of Aliyah and Integration

  • Tgst Levi

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

Reviewing Editor

  1. Xin Chen, Johns Hopkins University, United States

Version history

  1. Received: July 29, 2021
  2. Preprint posted: August 16, 2021 (view preprint)
  3. Accepted: March 17, 2022
  4. Accepted Manuscript published: March 21, 2022 (version 1)
  5. Accepted Manuscript updated: March 21, 2022 (version 2)
  6. Accepted Manuscript updated: March 22, 2022 (version 3)
  7. Version of Record published: April 1, 2022 (version 4)

Copyright

© 2022, Shore 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. Tikva Shore
  2. Tgst Levi
  3. Rachel Kalifa
  4. Amatzia Dreifuss
  5. Dina Rekler
  6. Ariella Weinberg-Shukron
  7. Yuval Nevo
  8. Tzofia Bialistoky
  9. Victoria Moyal
  10. Merav Yaffa Gold
  11. Shira Leebhoff
  12. David Zangen
  13. Girish Deshpande
  14. Offer Gerlitz
(2022)
Nucleoporin107 mediates female sexual differentiation via Dsx
eLife 11:e72632.
https://doi.org/10.7554/eLife.72632

Share this article

https://doi.org/10.7554/eLife.72632

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