Nucleoporin107 mediates female sexual differentiation via Dsx
- The Hebrew University, Israel
- Hebrew University Hadassah Medical School, Israel
- The Hadassah Hebrew University Medical Center, Israel
- Hadassah Hebrew University Medical Center, Israel
- 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
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Nucleoproin 107 Mediates Femae Sexual Differentiation via DoublesexNCBI Gene Expression Omnibus, GSE141094.
Article and author information
Author details
Funding
Israel Science Foundation (1788/15)
- David Zangen
- Offer Gerlitz
Israel Science Foundation (2295/19)
- 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
- Xin Chen, Johns Hopkins University, United States
Version history
- Received: July 29, 2021
- Preprint posted: August 16, 2021 (view preprint)
- Accepted: March 17, 2022
- Accepted Manuscript published: March 21, 2022 (version 1)
- Accepted Manuscript updated: March 21, 2022 (version 2)
- Accepted Manuscript updated: March 22, 2022 (version 3)
- 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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Nucleoporin107 mediates female sexual differentiation via Dsx
eLife 11:e72632.
https://doi.org/10.7554/eLife.72632
Further reading
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A crucial event in sexual reproduction is when haploid sperm and egg fuse to form a new diploid organism at fertilization. In mammals, direct interaction between egg JUNO and sperm IZUMO1 mediates gamete membrane adhesion, yet their role in fusion remains enigmatic. We used AlphaFold to predict the structure of other extracellular proteins essential for fertilization to determine if they could form a complex that may mediate fusion. We first identified TMEM81, whose gene is expressed by mouse and human spermatids, as a protein having structural homologies with both IZUMO1 and another sperm molecule essential for gamete fusion, SPACA6. Using a set of proteins known to be important for fertilization and TMEM81, we then systematically searched for predicted binary interactions using an unguided approach and identified a pentameric complex involving sperm IZUMO1, SPACA6, TMEM81 and egg JUNO, CD9. This complex is structurally consistent with both the expected topology on opposing gamete membranes and the location of predicted N-glycans not modeled by AlphaFold-Multimer, suggesting that its components could organize into a synapse-like assembly at the point of fusion. Finally, the structural modeling approach described here could be more generally useful to gain insights into transient protein complexes difficult to detect experimentally.
