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DMRT1 prevents female reprogramming in the postnatal mammalian testis

An Erratum to this article was published on 07 September 2011

This article has been updated

Abstract

Sex in mammals is determined in the fetal gonad by the presence or absence of the Y chromosome gene Sry, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells1. This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the fetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving WNT/β-catenin signalling2. In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogram granulosa cells into Sertoli cells2. Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor3 in mouse Sertoli cells, even in adults, activates Foxl2 and reprograms Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced and germ cells appear feminized. Thus Dmrt1 is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the fetal choice between male and female. Dmrt1 and Foxl2 are conserved throughout vertebrates4,5 and Dmrt1-related sexual regulators are conserved throughout metazoans3. Antagonism between Dmrt1 and Foxl2 for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of Dmrt1 also may help explain the aetiology of human syndromes linked to DMRT1, including disorders of sexual differentiation6 and testicular cancer7.

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Figure 1: DMRT1 maintains SOX9 and suppresses FOXL2 expression in postnatal Sertoli cells.
Figure 2: Sertoli-to-granulosa transdifferentiation in the adult testis.
Figure 3: Feminization of SCDmrt1KO XY gonads.
Figure 4: DMRT1 regulation of postnatal gene expression.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

mRNA expression profiling data have been deposited at the Gene Expression Omnibus under accession number GSE27261 and can be reviewed at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token5zlctbiugsamymtc&acc5GSE27261.

Change history

  • 03 August 2011

    Two typos in Fig. 3 and its legend have been corrected online but are incorrect in the print version.

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Acknowledgements

We thank M. Treier for helpful discussion, K. Hatzi, A. Minkina, A. Peterson, the University of Minnesota Mouse Genetics Laboratory and C. Small for technical assistance, J. Dean, R. Veitia and K.-i. Morohashi for antibodies, D. Greenstein and A. M. Weber-Main for comments on the manuscript, C. Manivel for histology expertise, M. Steffes and D. Gabrielson for oestradiol analysis, and the University of Minnesota Supercomputing Institute for computational resources. This work was funded by the NIH (GM59152), the Minnesota Medical Foundation, and a predoctoral fellowship from the NSF (to C.K.M.).

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Authors

Contributions

C.K.M. performed mouse breeding and analysis of protein and mRNA expression; M.W.M. performed ChIP analysis; A.L.S. performed bioinformatic analysis; C.K.M., D.Z. and V.J.B. designed the study, analysed data, and wrote the paper; M.D.G. provided mRNA profiling expertise; all authors discussed the results and edited the paper.

Corresponding authors

Correspondence to Vivian J. Bardwell or David Zarkower.

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The authors declare no competing financial interests.

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The file contains Supplementary Methods, Supplementary Tables 1-4, Supplementary Figures 1-11 with legends and additional references. (PDF 6402 kb)

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Matson, C., Murphy, M., Sarver, A. et al. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476, 101–104 (2011). https://doi.org/10.1038/nature10239

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