Division of spermatogonial stem cells 1 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 factors 2,3 . Here we show that the Ets related molecule 4 (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.
Estrogen receptor ␣ (ER␣) is essential for male fertility. Its activity is responsible for maintaining epithelial cytoarchitecture in efferent ductules and the reabsorption of fluid for concentrating sperm in the head of the epididymis. These discoveries and others have helped to establish estrogen's bisexual role in reproductive importance. Reported here is the molecular mechanism to explain estrogen's role in fluid reabsorption in the male reproductive tract. It is shown that estrogen regulates expression of the Na ؉ ͞H ؉ exchanger-3 (NHE3) and the rate of 22 Na ؉ transport, sensitive to an NHE3 inhibitor. Immunohistochemical staining for NHE3, carbonic anhydrase II (CAII), and aquaporin-I (AQP1) was decreased in ER␣ knockout (␣ERKO) efferent ductules. Targeted gene-deficient mice were compared with ␣ERKO, and the NHE3 knockout and CAIIdeficient mice showed ␣ERKO-like fluid accumulation, but only the NHE3 knockout and ␣ERKO mice were infertile. Northern blot analysis showed decreases in mRNA for NHE3 in ␣ERKO and antiestrogen-treated mice. The changes in AQP1 and CAII in ␣ERKO seemed to be secondary because of the disruption of apical cytoarchitecture. Ductal epithelial ultrastructure was abnormal only in ␣ERKO mice. Thus, in the male, estrogen regulates one of the most important epithelial ion transporters and maintains epithelial morphological differentiation in efferent ductules of the male, independent of its regulation of Na ؉ transport. Finally, these data raise the possibility of targeting ER␣ in developing a contraceptive for the male.
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