Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration.
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.
Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain.|Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
Francisco J
0000-0003-2651-1530
FJ
Barrionuevo
Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain.|Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
Alicia
A
Hurtado
Institute of Human Genetics, University of Freiburg, Freiburg, Germany.
Gwang-Jin
GJ
Kim
Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain.|Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
Francisca M
FM
Real
Departamento de Genética, Facultad de Ciencias, Universidad de Granada, Granada, Spain.
Mohammed
0000-0002-9079-8452
M
Bakkali
Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
Janel L
0000-0002-1875-3401
JL
Kopp
Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States.
Maike
M
Sander
Institute of Human Genetics, University of Freiburg, Freiburg, Germany.
Gerd
G
Scherer
Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain.|Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
Miguel
0000-0003-4446-9313
M
Burgos
Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain.|Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
Rafael
0000-0003-4103-8219
R
Jiménez
D000818:Animals; D054338:Cell Transdifferentiation; D005260:Female; D015870:Gene Expression; D006107:Granulosa Cells / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000502:physiology; D013737:Testis / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C110547:DMRT1 protein; D055758:SOX9 Transcription Factor; D055757:SOXE Transcription Factors; C498639:Sox8 protein, mouse; C527933:Sox9 protein, mouse; D014157:Transcription Factors
Sox8; Sox9; developmental biology; male-to-female genetic reprogramming; mouse; stem cells; testis degeneration