Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration

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Abstract

The new concept of mammalian sex maintenance establishes that particular key genes must remain active in the differentiated gonads to avoid genetic sex reprogramming, as described in adult ovaries after Foxl2 ablation. Dmrt1 plays a similar role in postnatal testes, but the mechanism of adult testis maintenance remains mostly unknown. Sox9 and Sox8 are required for postnatal male fertility, but their role in the adult testis has not been investigated. Here we show that after ablation of Sox9 in Sertoli cells of adult, fertile Sox8-/- mice, testis-to-ovary genetic reprogramming occurs and Sertoli cells transdifferentiate into granulosa-like cells. The process of testis regression culminates in complete degeneration of the seminiferous tubules, which become acellular, empty spaces among the extant Leydig cells. DMRT1 protein only remains in non-mutant cells, showing that SOX9/8 maintain Dmrt1 expression in the adult testis. Also, Sox9/8 warrant testis integrity by controlling the expression of structural proteins and protecting Sertoli cells from early apoptosis. Concluding, this study shows that, in addition to its crucial role in testis development, Sox9, together with Sox8 and coordinately with Dmrt1, also controls adult testis maintenance.

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Francisco J Barrionuevo

Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain

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The authors declare that no competing interests exist.
Alicia Hurtado

Departamento de Genética e Instituto de Biotecnología, University of Granada, Granada, Spain

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The authors declare that no competing interests exist.
Gwang-Jin Kim

Institute of Human Genetics, University of Freiburg, Freiburg, Germany

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The authors declare that no competing interests exist.
Francisca M Real

Max Planck Institute for Molecular Genetics, Berlin, Germany

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The authors declare that no competing interests exist.
Mohammed Bakkali

Departamento de Genética, Facultad de Ciencias, Universidad de Granada, Granada, Spain

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The authors declare that no competing interests exist.
Janel L Kopp

Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States

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The authors declare that no competing interests exist.
Maike Sander

Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States

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Gerd Scherer

Institute of Human Genetics, University of Freiburg, Freiburg, Germany

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The authors declare that no competing interests exist.
Miguel Burgos

Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain

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The authors declare that no competing interests exist.
Rafael Jiménez

Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain

For correspondence
rjimenez@ugr.es

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the guidelines for the protection of the animals used in scientific experimentation (Decree-Law 53/2013), dictated by the Spanish Ministry of Presidency. The protocol was approved by the Ethical Committee for Animal Experimentation of theUniversity of Granada (Ref. No.: 123-CEEA-UGR-2011). All surgery, except the BTB permeability experiment, was performed post-mortem after cervical dislocation. BTB experiment was performed under anesthesia for 30 min and then the animals were sacrificed without recovery. Every effort was made to minimize suffering.

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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.