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

Abstract

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.

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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.

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Acknowledgements

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.

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Correspondence to Kenneth M. Murphy.

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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.

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.

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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

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