ERM is required for transcriptional control of the spermatogonial stem cell niche


Division of spermatogonial stem cells1 produces daughter cells that either maintain their stem cell identity or undergo differentiation to form mature sperm. The Sertoli cell, the only somatic cell within seminiferous tubules, provides the stem cell niche through physical support and expression of surface proteins and soluble factors2,3. Here we show that the Ets related molecule4 (ERM) is expressed exclusively within Sertoli cells in the testis and is required for spermatogonial stem cell self-renewal. Mice with targeted disruption of ERM have a loss of maintenance of spermatogonial stem cell self-renewal without a block in normal spermatogenic differentiation and thus have progressive germ-cell depletion and a Sertoli-cell-only syndrome. Microarray analysis of primary Sertoli cells from ERM-deficient mice showed alterations in secreted factors known to regulate the haematopoietic stem cell niche. These results identify a new function for the Ets family transcription factors in spermatogenesis and provide an example of transcriptional control of a vertebrate stem cell niche.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Spermatogonial depletion and Sertoli-cell-only syndrome in ERM -/- mice.
Figure 2: Selective reduction of spermatogonia-specific genes in ERM -/- testes.
Figure 3: ERM expression in testis is restricted to Sertoli cells.
Figure 4: Failure of stem cell self-renewal causes spermatogonial depletion.


  1. 1

    Kubota, H., Avarbock, M. R. & Brinster, R. L. Spermatogonial stem cells share some, but not all, phenotypic and functional characteristics with other stem cells. Proc. Natl Acad. Sci. USA 100, 6487–6492 (2003)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Griswold, M. D. The central role of Sertoli cells in spermatogenesis. Semin. Cell Dev. Biol. 9, 411–416 (1998)

    CAS  Article  Google Scholar 

  3. 3

    Meng, X. et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1493 (2000)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Monte, D., Baert, J. L., Defossez, P. A., de Launoit, Y. & Stehelin, D. Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors. Oncogene 9, 1397–1406 (1994)

    CAS  Google Scholar 

  5. 5

    Seth, A. et al. The ets gene family. Cell Growth Differ. 3, 327–334 (1992)

    CAS  Google Scholar 

  6. 6

    Chotteau-Lelievre, A., Desbiens, X., Pelczar, H., Defossez, P. A. & de Launoit, Y. Differential expression patterns of the PEA3 group transcription factors through murine embryonic development. Oncogene 15, 937–952 (1997)

    CAS  Article  Google Scholar 

  7. 7

    Arber, S., Ladle, D. R., Lin, J. H., Frank, E. & Jessell, T. M. ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons. Cell 101, 485–498 (2000)

    CAS  Article  Google Scholar 

  8. 8

    Livet, J. et al. ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron 35, 877–892 (2002)

    CAS  Article  Google Scholar 

  9. 9

    Oulad-Abdelghani, M. et al. Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene. J. Cell Biol. 135, 469–477 (1996)

    CAS  Article  Google Scholar 

  10. 10

    Sassone-Corsi, P. Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296, 2176–2178 (2002)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Buaas, F. W. et al. Plzf is required in adult male germ cells for stem cell self-renewal. Nature Genet. 36, 647–652 (2004)

    CAS  Article  Google Scholar 

  12. 12

    De Franca, L. R. et al. Sertoli cells in testes containing or lacking germ cells: a comparative study of paracrine effects using the W (c-kit) gene mutant mouse model. Anat. Rec. 240, 225–232 (1994)

    CAS  Article  Google Scholar 

  13. 13

    Raible, F. & Brand, M. Tight transcriptional control of the ETS domain factors Erm and Pea3 by Fgf signalling during early zebrafish development. Mech. Dev. 107, 105–117 (2001)

    CAS  Article  Google Scholar 

  14. 14

    Colvin, J. S., Green, R. P., Schmahl, J., Capel, B. & Ornitz, D. M. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104, 875–889 (2001)

    CAS  Article  Google Scholar 

  15. 15

    Kiger, A. A., White-Cooper, H. & Fuller, M. T. Somatic support cells restrict germline stem cell self-renewal and promote differentiation. Nature 407, 750–754 (2000)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Tran, J., Brenner, T. J. & DiNardo, S. Somatic control over the germline stem cell lineage during Drosophila spermatogenesis. Nature 407, 754–757 (2000)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Costoya, J. A. et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nature Genet. 36, 653–659 (2004)

    CAS  Article  Google Scholar 

  18. 18

    Christensen, J. L., Wright, D. E., Wagers, A. J. & Weissman, I. L. Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol. 2, E75 (2004)

    Article  Google Scholar 

  19. 19

    Choong, M. L., Yong, Y. P., Tan, A. C., Luo, B. & Lodish, H. F. LIX: a chemokine with a role in hematopoietic stem cells maintenance. Cytokine 25, 239–245 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Molyneaux, K. A. et al. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development 130, 4279–4286 (2003)

    CAS  Article  Google Scholar 

  21. 21

    Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002)

    CAS  Article  Google Scholar 

  24. 24

    Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Ouyang, W. et al. The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc. Natl Acad. Sci. USA 96, 3888–3893 (1999)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Karl, A. F. & Griswold, M. D. Sertoli cells of the testis: preparation of cell cultures and effects of retinoids. Methods Enzymol. 190, 71–75 (1990)

    CAS  Article  Google Scholar 

Download references


We thank M. White for blastocyst microinjections; X. Cheng for helpful discussion; B. Sleckman for targeting vector; D. Ornitz, M. Griswold and K. Sheehan for reagents and antibody production; and T. Jessell for help with ERMIRES-LacZ mice. J.A.H. acknowledges funding from the Canadian Breast Cancer Research Alliance, the Canadian Institutes of Health Research and the DOD Breast Cancer Research Program. N.A.K. was supported by a DOD Breast Cancer Research Program Scholarship. K.M.M. is an investigator of the Howard Hughes Medical Institute.

Author information



Corresponding author

Correspondence to Kenneth M. Murphy.

Ethics declarations

Competing interests

Full Affymetrix data sets have been deposited with the Gene Expression Omnibus ( as accession series GSE2205. Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

Knockout construct and characterization.

Supplementary Figure S2

Histology of brain and lung.

Supplementary Figure S3

Expression of ERM in W/Wv mutant and Sertoli cells.

Supplementary Figure S4

Timing of ERM/LacZ expression.

Supplementary Figure S5

Characterization 3H7 antibody staining of ERM in Testis.

Supplementary Figure S6

Reduction of SDF-1 and CCL7 in ERM-/- testis.

Supplementary Figure Legends

Text to accompany the above Supplementary Figures.

Supplementary Tables

Supplementary Table S1-S5. Supplementary Table S1 is a gene chip of WT and knockout testes. Supplementary Table S2 is a quantization of TUNEL data. Supplementary Table S3 shows hormone levels for testosterone and FSH. Supplementary Table S4 is the gene chip data for isolated primary Sertoli cells. Supplementary Table S5 shows all the oligonucleotide primer sequences used for RT-PCR shown in the manuscript.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chen, C., Ouyang, W., Grigura, V. et al. ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436, 1030–1034 (2005).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing