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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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)
Griswold, M. D. The central role of Sertoli cells in spermatogenesis. Semin. Cell Dev. Biol. 9, 411–416 (1998)
Meng, X. et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1493 (2000)
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)
Seth, A. et al. The ets gene family. Cell Growth Differ. 3, 327–334 (1992)
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)
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)
Livet, J. et al. ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron 35, 877–892 (2002)
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)
Sassone-Corsi, P. Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296, 2176–2178 (2002)
Buaas, F. W. et al. Plzf is required in adult male germ cells for stem cell self-renewal. Nature Genet. 36, 647–652 (2004)
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)
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)
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)
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)
Tran, J., Brenner, T. J. & DiNardo, S. Somatic control over the germline stem cell lineage during Drosophila spermatogenesis. Nature 407, 754–757 (2000)
Costoya, J. A. et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nature Genet. 36, 653–659 (2004)
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)
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)
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)
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)
Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998)
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)
Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)
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)
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)
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.
Full Affymetrix data sets have been deposited with the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) as accession series GSE2205. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Knockout construct and characterization.
Histology of brain and lung.
Expression of ERM in W/Wv mutant and Sertoli cells.
Timing of ERM/LacZ expression.
Characterization 3H7 antibody staining of ERM in Testis.
Reduction of SDF-1 and CCL7 in ERM-/- testis.
Text to accompany the above Supplementary Figures.
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.
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). https://doi.org/10.1038/nature03894
Weighted Gene Correlation Network Meta-Analysis Reveals Functional Candidate Genes Associated with High- and Sub-Fertile Reproductive Performance in Beef Cattle
Progress in translational reproductive science: testicular tissue transplantation and in vitro spermatogenesis
Fertility and Sterility (2020)
Experimental diabetes negatively affects the spermatogonial stem cells’ self‐renewal by suppressing GDNF network interactions
Biology of Reproduction (2020)