Human DLC3 and Drosophila Cv-c function in testis development: using a model organism to analyse variations in sex development

  1. Sol Sotillos  Is a corresponding author
  2. Isabel von der Decken
  3. Ivan Domenech Mercadé
  4. Sriraksha Srinivasan
  5. Dmytro Sirokha
  6. Ludmila Livshits
  7. Stefano Vanni
  8. Serge Nef
  9. Anna Biason-Lauber  Is a corresponding author
  10. Daniel Rodríguez Gutiérrez
  11. James Castelli-Gair Hombría
  1. Centro Andaluz de Biología del Desarrollo, Spain
  2. University of Fribourg, Switzerland
  3. National Academy of Sciences of Ukraine, Ukraine
  4. University of Geneva, Switzerland

Abstract

Background: The identification of genes affecting gonad development is essential to understand the mechanisms causing Variations/Differences in Sex Development. Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients.

Methods: We have studied the requirement of cv-c, the Drosophila ortholog of DLC3, for Drosophila gonad development as well as the functional capacity of DLC3 human variants to rescue cv-c gonad defects. We show that Cv-c is required to maintain testis integrity during fly development.

Results: We find that Cv-c and human DLC3 can perform the same function in fly embryos, as flies carrying wild type but not patient DLC3 variations can rescue gonadal dysgenesis, suggesting a functional conservation. Expression of different Cv-c protein variants demonstrate that the StART domain mediates Cv-c's function in the male gonad independently from the GAP domain's activity.

Conclusions: This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART domain mediated function required to organize the gonadal mesoderm and maintain its interaction with the germ cells during testis development.

Funding: María de Maeztu Unit excellence grants MDM-2016-0687 and CEX-2020-001088-M. Ministerio de Ciencia e Innovación grant PID2019-104656GB-I00 cofunded by the European Regional Development Fund (FEDER). Swiss National Science Foundation (PP00P3_194807). Swiss National Supercomputing Centre under project ID s1132. European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 803952). Swiss National Science Foundation's Grant 320030-184807.Swiss National Science Foundation (grant number SCOPES IZ73Z0_152347/1) and National Academy of Sciences of Ukraine, project 'Molecular-Genetic Mechanisms of Human Disorders of Sexual Development' [0121U110054].

Data availability

All data generated during this study are included in the manuscript.

Article and author information

Author details

  1. Sol Sotillos

    Centro Andaluz de Biología del Desarrollo, Seville, Spain
    For correspondence
    ssotmar@upo.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4731-8107
  2. Isabel von der Decken

    Department of Endocrinology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Ivan Domenech Mercadé

    Department of Endocrinology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2115-8475
  4. Sriraksha Srinivasan

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Dmytro Sirokha

    Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine
    Competing interests
    The authors declare that no competing interests exist.
  6. Ludmila Livshits

    Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine
    Competing interests
    The authors declare that no competing interests exist.
  7. Stefano Vanni

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2146-1140
  8. Serge Nef

    Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5462-0676
  9. Anna Biason-Lauber

    Department of Endocrinology, University of Fribourg, Fribourg, Switzerland
    For correspondence
    anna.lauber@unifr.ch
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Rodríguez Gutiérrez

    Department of Endocrinology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  11. James Castelli-Gair Hombría

    Centro Andaluz de Biología del Desarrollo, Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.

Funding

Maria de Maetzu Unit Excellence grants (MDM-2016-0687)

  • James Castelli-Gair Hombría

Maria de Maetzu Unit Excellence grants (CEX-2020-001088-M)

  • James Castelli-Gair Hombría

Ministerio de Ciencia, Innovación y Universidades (PID2019-104656GB-I00)

  • James Castelli-Gair Hombría

Swiss National Science Foundation (PP00P3_194807)

  • Stefano Vanni

Swiss National Supercomputing Center (s1132)

  • Stefano Vanni

H2020 European Research Council (803952)

  • Stefano Vanni

Swiss National Science Foundation (SCOPES IZ73Z0_152347/1)

  • Ludmila Livshits

National Academy of Sciences of Ukraine (0121U110054)

  • Ludmila Livshits

Swiss National Science Foundation (320030-184807)

  • Anna Biason-Lauber

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

Reviewing Editor

  1. Erika A Bach, New York University School of Medicine, United States

Ethics

Human subjects: All clinical investigations were performed according to the declaration of Helsinki principles. The study was approved by the Geneva ethical committee CCER, authorization number 14-121. The patients and/or their legal guardians gave informed written consent to the study.

Version history

  1. Preprint posted: August 1, 2022 (view preprint)
  2. Received: August 1, 2022
  3. Accepted: October 25, 2022
  4. Accepted Manuscript published: November 3, 2022 (version 1)
  5. Version of Record published: November 21, 2022 (version 2)

Copyright

© 2022, Sotillos 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. Sol Sotillos
  2. Isabel von der Decken
  3. Ivan Domenech Mercadé
  4. Sriraksha Srinivasan
  5. Dmytro Sirokha
  6. Ludmila Livshits
  7. Stefano Vanni
  8. Serge Nef
  9. Anna Biason-Lauber
  10. Daniel Rodríguez Gutiérrez
  11. James Castelli-Gair Hombría
(2022)
Human DLC3 and Drosophila Cv-c function in testis development: using a model organism to analyse variations in sex development
eLife 11:e82343.
https://doi.org/10.7554/eLife.82343

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https://doi.org/10.7554/eLife.82343