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Sex reversal following deletion of a single distal enhancer of Sox9
Open accessAbstract
Sox9 regulation during sex determination: Sex determination is regulated by the Sox9 gene. During testis differentiation, this gene is directly targeted by the product of the Y chromosome–encoded gene Sry . The regulatory region of Sox9 is complex, which is typical of genes with multiple roles in development. Gonen et al. find that a single far-upstream 557–base pair element is critical for up-regulating Sox9 . Without it, XY mice develop as females instead of males. The 557–base pair enhancer is conserved, likely to be relevant to human disorders of sex differentiation, and probably essential because it acts early in a time-critical process, and any failure allows ovary-specific factors to dominate. Science , this issue p. 1469
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“it was recently shown that deletion of a relatively weak distal enhancer in the mouse Sox9 sex determination locus leads to sex reversal, while the phenotypic effects of deleting stronger and more proximal Sox9 enhancers are much less pronounced [510].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [510]
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Items 101–189 of 189
Epigenetic control of SOX9 gene by the histone acetyltransferase P300 in human Sertoli cells
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“…activation, we examined three regulatory regions of the Sox9 gene: a region close to the transcription start site (mTSS), as described by Chen et al. in 2015 [22]; and a region spanning the Sox9 binding site in the TESCO and enhancer 13 enhancers, as described by Gonen et al., in 2018 [23] (Suppl.”
MethodSex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysisPreprint
Mota-Gómez, I., Rodríguez, J. A., Dupont, S. M., Lao, O., Jedamzick, J., Kuhn, R., Lacadie, S., Garcia-Moreno, S. A., Hurtado, A., Acemel, R. D., et al. (2022) · bioRxiv · doi:10.1101/2022.11.18.516861 · Cited by 9
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“In our present study, the expression levels of SOX9, DHH, and FSHR were affected in GDM male offspring.”
BackgroundInfluentialRegulation of Sox8 through lncRNA Mrhl-Mediated Chromatin Looping in Mouse Spermatogonia
Kayyar, B., Ravikkumar, A. C., Bhaduri, U., & Rao, M.-R.-S. (2021) · bioRxiv · doi:10.1128/mcb.00475-21 · Cited by 9
“Sox9 is regulated by multiple tissue specific enhancers and in the testis alone, is regulated by multiple enhancers acting either redundantly or synergistically (Gonen et al, 2018, Croft et al, 2018).”
BackgroundMammalian haploid stem cells: establishment, engineering and applications
He, W., Chen, J., & Gao, S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03069-6 · Cited by 11
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Qian, Z.-Y., Grand, K. L., Freedman, A., Nieto, M. C., Behlmann, A., Schweiger, B., & Sanchez-Lara, P. (2021) · American Journal of Medical Genetics. Part A · doi:10.1002/ajmg.a.62373 · Cited by 8
“Enh13 deletion and CNVs of XYSR were shown to cause XY sex reversal due to reduced SOX9 expression (Croft, Ohnesorg, Hewitt, Bowles, Quinn, Tan, Corbin, Pelosi, van den Bergen, Sreenivasan, Knarston, et al., 2018; Gonen et al., 2018).”
BackgroundRoscito, J. G., Subramanian, K., Naumann, R., Sarov, M., Shevchenko, A., Bogdanova, A. I., Kurth, T., Foerster, L. C., Kreysing, M., & Hiller, M. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msaa212 · Cited by 9
“Although perturbations or deletions of single regulatory elements can result in drastic (Chan et al. 2010; Kvon et al. 2016; Gonen et al. 2018) or subtle phenotypic changes (Cretekos et al. 2008; Capellini et al. 2017; Thompson et al. 2018), they most often do not result in a detectable phenotype…”
A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development
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Self-citationGATA4 binding to the Sox9 enhancer mXYSRa/Enh13 is critical for testis differentiation in mouse
Ogawa, Y., Tsuchiya, I., Yanai, S., Baba, T., Morohashi, K.-I., Sasaki, T., Sasaki, J., Terao, M., Tsuji-Hosokawa, A., & Takada, S. (2025) · Communications Biology · doi:10.1038/s42003-025-07504-2 · Cited by 7
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders
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Jiang, Q.-H., Xu, D., Wang, M.-E., Xie, X., & Zhu, D.-F. (2023) · Fishes · doi:10.3390/fishes8070351 · Cited by 7
Chen, Y.-S., Racca, J. D., & Weiss, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.945030 · Cited by 7
“regulated by upstream testis-specific enhancer elements: Enh13 (17) (blue) and TESCO (16) (light gray).”
BackgroundMethodInfluentialHu, X., Wang, H., Tian, G. G., Hou, C., Xu, B., Zhao, X., Zhao, Y., Fang, Q., Li, X., He, L., et al. (2022) · Cell & Bioscience · doi:10.1186/s13578-021-00697-z · Cited by 7
An Enhancer-Based Analysis Revealed a New Function of Androgen Receptor in Tumor Cell Immune Evasion
Wang, Y., Li, J., Li, J., Li, P., Wang, L., & Di, L. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.595550 · Cited by 8
Protection Against XY Gonadal Sex Reversal by a Variant Region on Mouse Chromosome 13
Livermore, C., Simon, M., Reeves, R., Stévant, I., Nef, S., Pope, M., Mallon, A., Wells, S., Warr, N., & Greenfield, A. (2019) · Genetics · doi:10.1534/genetics.119.302786 · Cited by 7
Neural crest gene regulatory networks as drivers of development, diversification and disease
Štundl, J., Raja, D. A., & Bronner-Fraser, M. E. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-00949-1 · Cited by 8
Chen, Y.-Y., Rodriguez, K., Alexander, A. K., Xu, X., Papas, B. N., Estermann, M., & Yao, H. (2025) · bioRxiv · doi:10.1126/sciadv.aea7403 · Cited by 6
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Lats1 and Lats2 regulate YAP and TAZ activity to control the development of mouse Sertoli cells
Nader, N. A., Charrier, L., Meisnsohn, M.-C., Banville, L., Deffrennes, B., St-Jean, G., Boerboom, D., Zamberlam, G., Brind'Amour, J., Pépin, D., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202400346r · Cited by 6
“6,7 12 The primary target of SRY is sex determining region Y-box 9 ( Sox9 ), 13,14 which regulates a set of genes similar to the one regulated by SRY.”
BackgroundWang, X., Chen, G., Du, Y., Yang, J., & Wang, W. (2023) · Kidney & Blood Pressure Research · doi:10.1159/000533544 · Cited by 6
“Diseases associated with Sox9 include the search for abnormal curved limb development [10] and X/Y sex reversal [11].”
BackgroundOkashita, N., Maeda, R., & Tachibana, M. (2023) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2221499120 · Cited by 6
Novel biological insights revealed from the investigation of multiscale genome architecture
Ding, T., & Zhang, H. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.12.009 · Cited by 7
Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex
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Long-Range Regulation of Key Sex Determination Genes
Migale, R., Neumann, M., & Lovell-Badge, R. H. (2021) · Sexual Development · doi:10.1159/000519891 · Cited by 12
“These shared genes were mostly involved in Sertoli cell adhesion, tight junction dynamics, and actin cytoskeleton signaling, suggesting that SRY and SOX9 may cooperate in establishing early testis cord formation, with SOX9 possibly taking over the role after Sry has been switched off, at least in the mouse.”
BackgroundResultInfluentialSelf-citationThe molecular genetic basis of fetal granulosa cell development
Greenfield, A. (2021) · doi:10.1016/j.coemr.2020.11.010 · Cited by 6
Generation and mutational analysis of a transgenic mouse model of human SRY
Thomson, E., Zhao, L., Chen, Y.-S., Longmuss, E., Ng, E.-T., Sreenivasan, R., Croft, B., Song, X., Sinclair, A., Weiss, M., et al. (2021) · bioRxiv · doi:10.1002/humu.24318 · Cited by 6
“SRY binds to the SOX9 enhancers TESCO and Enh13 in mice, activating expression within the bipotential gonad (Croft et al., 2018; Gonen et al., 2018; Sekido & Lovell‐Badge, 2008).”
BackgroundMiura, K., Harikae, K., Nakaguchi, M., Imaimatsu, K., Hiramatsu, R., Tomita, A., Hirate, Y., Kanai-Azuma, M., Kurohmaru, M., Ogura, A., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0212367 · Cited by 6
From Enrico Sertoli to freemartinism: the many phases of the master testis-determining cell
Yao, H., & Rodriguez, K. (2023) · Biology of Reproduction · doi:10.1093/biolre/ioad037 · Cited by 5
“SRY induces Sox9 expression by binding to the enhancer element TESCO (testis-specific enhancer of Sox9 core), Enh13, and other regions upstream of the transcription start site of Sox9 [13, 16].”
BackgroundInfluentialFrancese-Santos, A. P., Meinel, J., Piveta, C. S. C., Andrade, J., Barros, B. A., Fabbri-Scallet, H., Gil-da-Silva-Lopes, V., Guerra-Júnior, G., Künstner, A., Busch, H., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010494 · Cited by 5
“When Xp duplication occurs, overexpression of NR0B1 disrupts NR5A1 binding to its DNA targets and prevents coactivation at the Sox9 promoter and enhancers [18,19] leading to dysgenetic testes, streak gonads or sex reversal in mice [4,5,16,20].”
BackgroundTranscriptional profile and chromatin accessibility in zebrafish melanocytes and melanoma tumors
Kramer, E. T., Godoy, P. M., & Kaufman, C. K. (2021) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkab379 · Cited by 5
“…mutations, gene expression changes only, or have used human or zebrafish cell lines rather than focusing on in vivo animal models (Yen et al. 2013; Haltaufderhyde and Oancea 2014; Kaufman et al. 2016; Badal et al. 2017; Kunz et al. 2018; Venkatesan et al. 2018; Marie et al. 2020; Wouters et al.…”
BackgroundThiecke, M. J., Wutz, G., Muhar, M., Tang, W., Bevan, S., Malysheva, V., Stocsits, R. R., Neumann, T., Zuber, J., Fraser, P., et al. (2020) · bioRxiv · doi:10.1101/2020.02.10.941989 · Cited by 5
“It may also explain phenomena, whereby a weak distal enhancer, but not a strong proximal one, is required for developmental activation of sex-determining gene Sox9 (Gonen et al., 2018).”
BackgroundHogan, P. G., Reveles, B. V., & Arteaga-Vazquez, L. J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1576468 · Cited by 6
“Further underscoring the existence of threshold concentrations, SOX9 is expressed naturally, but at lower levels, in XX-genotype genital ridges that go on to develop into ovaries (86); and overexpression of SOX9 redirects XX genital ridges to develop into testes (88, 89).”
InfluentialRacca, J. D., Chen, Y.-S., Brabender, A. R., Battistin, U., Weiss, M. A., & Georgiadis, M. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107683 · Cited by 4
“Relative SRY occupancies of testis-speci fi c enhancers Enh13 and TESCO are summarized in Figure 6 A .”
BackgroundKaplan, S. J., Wong, W., Yan, J., Pulecio, J., Cho, H., Li, Q., Zhao, J., Leslie-Iyer, J., Kazakov, J., Murphy, D., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114640 · Cited by 16
“91-99 These enhancers are valuable models for further investigation into long-range transcriptional regulation and its implications for health and disease.”
Hirata, Y., Mizushima, S., Mitsukawa, S., Kon, M., Kuroki, Y., Jogahara, T., Shinohara, N., & Kuroiwa, A. (2023) · Cytogenetic and Genome Research · doi:10.1159/000536408 · Cited by 3
“…we performed a reporter gene assay using COS7 cells. mEnh8 showed female-speci fi c enhancer activity in a previous in vivo reporter gene assay [7], whereas mEnh8 activity was observed when co-transfected with mouse SOX9 (mSOX9) only or a combination of NR5A1 and mSOX9 in the present study…”
BackgroundMethodInfluentialSex-biased genome-editing effects of CRISPR-Cas9 across cancer cells dependent on p53 status
Guo, M., & Xiong, Y.-Y. (2023) · iScience · doi:10.1016/j.isci.2023.107529 · Cited by 4
“Third, SOX9 on chromosome 17 is a direct target of SRY (Sex-Determining Region Y) and, together with its distal enhancer, is critical in mammalian sex determination.(29) SOX9 can regulate MYC expression by interacting with FOXC1.”
Estermann, M., & Smith, C. (2022) · bioRxiv · doi:10.3389/fcell.2022.1042759 · Cited by 4
Li, H., He, J., & Leong, I. (2021) · Medicine · doi:10.1097/md.0000000000024641 · Cited by 4
“5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.([8]) Coincidentally, bioinformatic analysis identified three putative enhancers for SOX9 that responded todifferent combinationsof testis-specific regulators.”
BackgroundRegulation of the Sox3 Gene in an X0/X0 Mammal without Sry, the Amami Spiny Rat, Tokudaia osimensis
Washio, K., Mizushima, S., Jogahara, T., & Kuroiwa, A. (2019) · Cytogenetic and Genome Research · doi:10.1159/000504313 · Cited by 4
Spiny rat SRY lacks a long Q‐rich domain and is not stable in transgenic mice
Ogata, Y., Nishikata, M., Kitada, K., Mizushima, S., Jogahara, T., & Kuroiwa, A. (2019) · Developmental Dynamics · doi:10.1002/dvdy.73 · Cited by 4
“Several enhancers are targeted by SRY proteins.(5,6) TESCO (TES [testis-specific enhancer of Sox9] COre) was first reported as a regulatory element that up-regulates the expression of Sox9 by binding SRY proteins together with SF1 (also referred to as NR5A1: nuclear receptor subfamily 5, group A, member 1).”
BackgroundCBX2 is required during male sex determination to repress female fate at bivalent loci
Garcia-Moreno, S. A., Lin, Y.-T., Futtner, C., Salamone, I. M., Maatouk, D. M., & Capel, B. (2018) · bioRxiv · doi:10.1101/496984 · Cited by 4
“Mice The Sox9-CFP, TESm-CFP and Sf1-eGFP reporter mouse lines, and the Cbx2, Fgf9 and Wnt4 KO mouse lines were previously generated [30, 34-36, 43] and maintained on a C57BL/6”
MethodSelf-citationYang, Y., & Wilson, M. (2018) · bioRxiv · doi:10.1101/347880 · Cited by 4
Chromatin spatial analysis by METALoci unveils sex-determining 3D regulatory hubs
Mota-Gómez, I., Rodríguez, J. A., Dupont, S. M., Hurtado, A., Cadenas, V., Zuber, L., Maceda, I., Lao, Ó., Jedamzick, J., Kühn, R., et al. (2026) · Yearbook of pediatric endocrinology · doi:10.1038/s41594-026-01749-z · Cited by 16
Self-citationLakshmipathi, M., Dartée, N., Puchkina, A., Santos, M. D. L., de Bruin, I. J., Hamer, G., van Pelt, A. M. M., Lopes, S. M. C. D. S., Mulder, C. L., & Baarends, W. M. (2025) · Human Reproduction Update · doi:10.1093/humupd/dmaf012 · Cited by 2
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“We imagine that this lifetime in vitro determines in turn the cellular lifetime of one or more SRY-dependent and testis-speci fi c enhanceosomes in far-upstream region of the SOX9 gene (Figure 1D) (5, 6, 76).”
InfluentialXu, Y., Cui, S., Li, T., Du, Z.-H., Ning, F.-Y., Jiang, H., Bai, X.-J., Wang, X., & Bao, J. (2022) · Animals · doi:10.3390/ani12202887 · Cited by 3
“SOX9 is a critical gene in mammals for sex determination, and loss of SOX9 expression or its inappropriate activation can lead to XY female development and XX male development in humans and mice, respectively [17].”
BackgroundWang, N., Zhu, W.-J., Han, B., Wang, H., Zhu, H., Chen, Y.-C., Chen, Y., Liu, J.-H., Liu, Y., Zhao, S.-X., et al. (2020) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/clinem/dgaa109 · Cited by 3
Evolution of sex determination mechanisms and sex chromosomes
Wu, R., Xu, X., & Zhou, Q. (2019) · Scientia Sinica Vitae · doi:10.1360/n052018-00208 · Cited by 3
“[43] Gonen N, Futtner C R, Wood S, et al.”
BackgroundGenome-wide analysis of Chongqing native intersexual goats using next-generation sequencing
E, G., Jin, M.-L., Zhao, Y., Li, X.-L., Li, L.-H., Yang, B.-G., Duan, X.-H., & Huang, Y.-F. (2019) · 3 Biotech · doi:10.1007/s13205-019-1612-0 · Cited by 3
Genetic evaluation of disorders of sex development: current practice and novel gene discovery
Kremen, J., & Chan, Y.-M. (2018) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000452 · Cited by 5
Reconstruction of the global neural crest gene regulatory network in vivo
Williams, R. M., Candido-Ferreira, I., Repapi, E., Gavriouchkina, D., Senanayake, U., Telenius, J., Taylor, S., Hughes, J., & Sauka-Spengler, T. (2018) · bioRxiv · doi:10.1101/508473 · Cited by 3
“, 2014; Levine and Davidson, 2005), that can be located hundreds of kilobases away from their target promoters such as the Sox9 distal enhancer (Gonen et al., 2018) and within large and often repeat-rich genomes (Prescott et al.”
BackgroundEnhancer Trajectories in Lineage Commitment: Regulatory Logic of States and Cooperation
Oh, M., Jeong, S., Kang, K., & Kim, S.-K. (2026) · Biomolecules · doi:10.3390/biom16010087 · Cited by 5
“At the Sox9 testis locus, deletion of a single distal enhancer (Enh13) is sufficient to cause sex reversal despite the presence of additional testis enhancers, exemplifying a non-redundant, gatekeeper-like enhancer rather than one unit in an additive pool [175].”
Gonadal sex reversal at single-cell resolution in Znrf3-deficient mice
Kay, R. G. G., Reeves, R., Siggers, P., Greenaway, S., Mallon, A., Wells, S. E., Koo, B., Mayère, C., Nef, S., Greenfield, A., et al. (2024) · Development · doi:10.1242/dev.202707 · Cited by 2
The single-cell chromatin landscape in gonadal cell lineage specification
Suen, H. C., Ou, F., Miu, K.-K., Wang, Z., Chan, W., & Liao, J. (2024) · BMC Genomics · doi:10.1186/s12864-024-10376-1 · Cited by 5
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“Therefore, SRY may upregulate the endogenous Sox9 gene, which would contribute to the Rspo1 repression [2, 8, 46, 47].”
BackgroundStévant, I., Gonen, N., & Poulat, F. (2023) · bioRxiv · doi:10.1101/2023.10.23.563600 · Cited by 2
“5 the expression of the transcription factor SOX9, (Gonen et al. 2018) which in turn controls Sertoli cells differentiation (review: (Vining et al. 2021)).”
BackgroundSelf-citationHow to manage without a Y chromosome
Schartl, M., & Lamatsch, D. (2023) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2218839120 · Cited by 2
“The duplicated fragment contains a sequence, Enh14, that was earlier identified in the mouse as a putative enhancer of Sox9 (17).”
BackgroundHan, H.-Y., Yang, S., Li, J., Zhao, J., Wei, H.-F., Si, H., Li, W.-T., Li, C.-C., & Quan, K. (2021) · Veterinary Medicine and Science · doi:10.1002/vms3.672 · Cited by 2
“For example, inmice, the SRY gene specifically upregulates SOX9 expression in the early stage of sex differentiation (Gonen et al., 2018).”
BackgroundNon-Coding Genome, Transcription Factors, and Sex Determination
Poulat, F. (2021) · Sexual Development · doi:10.1159/000519725 · Cited by 5
Self-citationA comprehensive study of disorder of sex development in Staffordshire bull terrier dog.
Horňáková, L., Dianovskỳ, J., Holečková, B., & Šiviková, K. (2019) · Reproduction in domestic animals = Zuchthygiene · doi:10.1111/rda.13429 · Cited by 2
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Non-canonical enhancers control gene expression and cell fate in human pluripotent stem cellsPreprint
Cao, Y., Dovgusha, O., Ebrahımı, A., Bevan, S., Widmer, L., Torabi, F., Kurlovich, J., Rodríguez-Polo, I., Khan, S., Patel, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.01.657118
“Highlighting their importance in development, aberrant enhancer function or ectopic enhancer activation can lead to severe developmental malformations 6–8 .”
[Sex determination, it is all about timing].
Gregoire, E., Cian, M. D., Detti, M., Gillot, I., Perea-Gomez, A., & Chaboissier, M.-C. (2024) · Medecine sciences : M/S · doi:10.1051/medsci/2024095 · Cited by 1
Tissue- and/or Temporal-Specific Mutations in Mice Using Conditional Alleles.
Papaioannou, V. E., & Behringer, R. R. (2023) · Cold Spring Harbor Protocols · doi:10.1101/pdb.over107980 · Cited by 1
Disorders of sexual development in 46,XX individuals: an update
Guerra, M., Céspedes, C., Forero, C., Suárez-Obando, F., & Rojas, A. (2021) · Revista Mexicana de Urología · doi:10.48193/rmu.v81i4.800 · Cited by 1
The Role of the Ste20-like Kinase in Embryonic Development and Neu-induced Mammary Tumorigenesis
Al‐Zahrani, K. N. (2018) · uO Research (University of Ottawa) · doi:10.20381/ruor-22866
DMRT1 is required at two steps of ovarian differentiation in rabbits
Dujardin, É., Poulat, F., Barberá-Aura, I., Dewaele, A., André, M., McKey, J., Gras, S., Aubert-Frambourg, A., Jouneau, L., Lupiáñez, D. G., et al. (2026) · Science Advances · doi:10.1126/sciadv.aeh1087
Self-citationAndrogens Drive SOX9 Upregulation in Injured Proximal Tubular Cells.
Allison, C. V., Patel, P. S., Qiao, X.-Y., Stayton, A., Mondal, M., Silvaroli, J., Karel, I. Z., Thorson, V. C., Sloane, G., Thailammanal, H. J., et al. (2026) · Kidney International · doi:10.1016/j.kint.2026.07.038
Strain‐Dependent Functional Variation of a Sex Specific Sox9 Enhancer
Tsuchiya, I., Tsuji-Hosokawa, A., Furuhashi, S., Sugiyama, K., Ogawa, Y., Oishi, A., Terao, M., & Takada, S. (2026) · Genes to Cells · doi:10.1111/gtc.70131
“…additional regulatory elements contribute to Sox9 expression during testis differentiation, such as Enh14, which exhibits testis-specific activity (Gonen et al. 2018) and is involved in the sex determination of Tokudaia osimensis (Terao XY mice lacking the entire Enh13/mXYSRa region developed as…”
Chen, W.-J., Chen, D., Lin, S.-Y., Cai, G.-J., Li, W.-B., Deng, Z.-Y., Xie, Z.-H., Zhang, M., Han, C., & Li, Q. (2026) · Gene Reports · doi:10.1016/j.genrep.2026.102469
Female mice grow testes after this single DNA tweak.
Fieldhouse, R. (2026) · Nature · doi:10.1038/d41586-026-01120-8
Charting the 3D regulatory landscape of sex determination with geostatistics.
(2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-026-01750-6
Chick gonad explant electroporation reveals enhancers for testes determining factor, DMRT1
Oberholzer, Z., Taylor, G., Hockman, D., & Nikitina, N. V. (2026) · Developmental Biology · doi:10.1016/j.ydbio.2026.03.011
Ma, W.-J., Fontserè, R., Cornelis, T., Veltsos, P., & Zhou, Q. (2026) · doi:10.48550/arxiv.2602.23624
“…results in loss or failure of Sox9 up-regulation and a robust male-to-female gonadal sex reversal, with supporting cells adopting the female development pathway such as granulosa-like identity and ovaries forming instead of testes (Gonen et al., 2018; Koopman et al., 1991; Lavery et al., 2011).”
Male fertility is independent of Enh13 control of Sox9 testicular expression
Lubman, M., Ridnik, M., Stévant, I., Djanshvili, Y. K., Abberbock, E., Lhermann, S. Z., & Gonen, N. (2026) · Development · doi:10.64898/2026.02.09.704748 · Cited by 1
“In this study, we show that early conditional deletion of Enh13 results in a fully penetrant XY sex-reversal phenotype, indistinguishable from that caused by complete loss of Enh13 (Gonen et al. 2018) or loss of the Sox9 gene itself (Chaboissier et al. 2004; Lavery et al. 2011).”
InfluentialSelf-citationAndrogens Drive SOX9 Upregulation in Injured Proximal Tubular Cells
Allison, C. V., Patel, P. S., Qiao, X.-Y., Stayton, A., Silvaroli, J., Karel, I. Z., Thorson, V. C., Sloane, G., Thailammanal, H. J., Scindia, Y., et al. (2025) · bioRxiv · doi:10.1101/2025.10.23.684153
“SOX9 is also a master regulator of sex determination 58 and nephrogenesis 34 , and whether sex differences in developmental SOX9 activity contribute to disparities in nephron endowment and kidney size between males and females remains unknown.”
Mitsukawa, S., Mizushima, S., Kimura, Y., & Kuroiwa, A. (2025) · Genes & Genetic Systems · doi:10.1266/ggs.25-00024
Temporal misexpression of En1 during limb development causes distinct phenotypesPreprint
Ringel, A. R., Magg, A., Benetti, N., Schöpflin, R., Kühnlein, M., Stiege, A. C., Fischer, U., Wittler, L., Lorenz, S., Mundlos, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.06.606766 · Cited by 1
“A complex regulatory architecture with inter-dependencies on multiple cis regulatory elements in vivo has been reported only for few genes including Sox9 17 .”
Background[Dmrt1 is a major gene for testicular determination and for male and female fertility in rabbits].
Dujardin, É., Pannetier, M., & Pailhoux, É. (2024) · Medecine sciences : M/S · doi:10.1051/medsci/2024004
gjSOX9 Cloning, Expression, and Comparison with gjSOXs Family Members in Gekko japonicus
Huang, X.-Z., Zhao, R., Xu, Z.-W., Fu, C., Xie, L., Li, S.-R., Wang, X., & Zhang, Y.-P. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45110584
“Another investigation showed that the deletion of 5 (cid:48) distal enhancer13 (Enh13) from the SOX9 gene led to complete XY male-to-female sex reversal, indicative of SOX9 (cid:48) s crucial roles in testis development in mice [10].”
BackgroundGuo, M., & Xiong, Y.-Y. (2023) · bioRxiv · doi:10.1101/2022.08.03.502574
“Third, SOX9 on 141 chromosome 17 is a direct target of SRY (Sex-Determining Region Y) and, together with its 142 distal enhancer, is critical in mammalian sex determination [31].”
BackgroundTRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
Rossitto, M., Déjardin, S., Rands, C. M., Gras, S. L., Migale, R., Rafiee, M.-R., Neirijnck, Y., Pruvost, A., Nguyen, A., Bossis, G., et al. (2022) · bioRxiv · doi:10.1101/2021.03.24.436749
Self-citationVaiani, E., Chen, Y.-S., Ramírez, P., Racca, J. D., Baquedano, M., Malosetti, C., Touzon, M., Marino, R., Costanzo, M., Bailez, M., et al. (2021) · bioRxiv · doi:10.1101/2021.05.05.442859
Chen, Y.-S., Racca, J. D., Amir, D., Haas, E., & Weiss, M. (2021) · bioRxiv · doi:10.1101/2021.05.05.442830
“(10,11): this regulatory axis orchestrates programs of cell-cell communication, migration and differentiation leading to testis formation (12,13).”
BackgroundResultPKA drives paracrine crisis and WNT4-dependent testis tumor in Carney complexPreprint
Djari, C., Sahut-Barnola, I., Septier, A., Plotton, I., Montanier, N., Dufour, D., Levasseur, A., Wilmouth, J., Pointud, J.-C., Faucz, F., et al. (2020) · bioRxiv · doi:10.1101/2020.12.21.423735
Organizational properties of a functional mammalian cis-regulome
Chaudhri, V. K., Dienger-Stambaugh, K., Wu, Z., Shrestha, M., & Singh, H. (2018) · bioRxiv · doi:10.1101/550897
“The median distance for the murine genome is 495kb. Recent evidence has established the ability of enhancers to act over long distances ranging from 0.5 to 1.5Mb (Claussnitzer et al., 2015; Gonen et al., 2018; Johnson et al., 2018).”
BackgroundInfluentialStudies of B cell development and V(D)J recombination
Chovanec, P. (2019) · doi:10.17863/cam.35588
“167 the levels of Sox9 expression in XY males below the required levels for testes development, leading to a sex reversal phenotype (Gonen et al., 2018).”
Background
Metadata
- Authors
- Gonen, N., Futtner, C. R., Wood, S., Garcia-Moreno, S. A., Salamone, I. M., Samson, S. C., Sekido, R., Poulat, F., Maatouk, D. M., & Lovell-Badge, R.
- Affiliations
- The Francis Crick Institute (GB)
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA.
- Northwestern University (US)
- University of Aberdeen (GB)
- Department of Genetics and Development, Institute of Human Genetics, CNRS-University of Montpellier UMR9002, Montpellier, France.
- Corresponding author
- Maatouk, Danielle M.
- Lovell-Badge, Robin
- ORCID
- Venue
- Science
- Published
- 2018-06-29
- Volume
- 360
- Issue
- 6396
- Pages
- 1469-1473
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6034650
- OpenAlex
- W2808131961
- Cited by
- 235
- References
- 46
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 24 · 2023: 27 · 2022: 42 · 2021: 33 · 2020: 28 · 2019: 32 · 2018: 16
- FWCI
- 16.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Northwestern Medical Faculty Foundation, Inc.
- Francis Crick Institute
- Agence Nationale de la Recherche
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SOX9, sex determination, sex reversal, distal enhancers, SRY, testicular differentiation, XY females, disorders of sex development, gene expression regulation
- MeSH terms
- Animals, Enhancer Elements, Genetic, Female, Gonadal Dysgenesis, 46,XY, Humans, Male, Testis, Conserved Sequence, Sequence Deletion, Sex Determination Processes, Transcription Initiation Site, Mice, Sex-Determining Region Y Protein, SOX9 Transcription Factor
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