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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.

Gads is a SH2 and SH3 domain-containing, hematopoietic-specific adaptor protein that functions in signalling from the T cell receptor. Gads acts by linking SLP-76, bound by the carboxy-terminal Gads SH3 domain, to tyrosine phosphorylated LAT which contains binding sites for the Gads SH2 domain. Gads is distinguished from Grb2 and the closely related Grap protein by the presence of a 120 amino acid unique region between the SH2 domain and the carboxy terminal SH3 domain. Here we demonstrate that the unique region of Gads contains a capase cleavage site. Induction of apoptosis in lymphocytes results in detectable Gads cleavage by 60 min. Gads cleavage is blocked in vivo by treating cells with a caspase 3 inhibitor. A putative caspase 3 cleavage site was identified within the unique region and mutation of this site prevented Gads cleavage in vitro, and in vivo. The Gads cleavage products retained the predicted binding specificity for SLP-76 and LAT. Expression of the Gads cleavage products in Jurkat T cells inhibited NFAT activation following TCR cross linking. These findings indicate that cleavage of Gads in vivo could function to alter signalling downstream of the T cell receptor by disrupting cross talk between SLP-76 and LAT.

Nature 378, 303–306 (1995) IN the legend to Fig. 4 of this Letter, the designations for rf2 and rf3 were confused: bold hatching represents rf2 and light hatching rf3.