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J. Cell Biol.,
Volume 145, Number 5, May 31, 1999 1027-1038
* Department of Histology and Medical Embryology, University of Rome "La Sapienza," 00161 Rome, Italy; and The potent smooth muscle agonist endothelin-1 (ET-1) is involved in the local control of seminiferous tubule contractility, which results in the forward
propulsion of tubular fluid and spermatozoa, through
its action on peritubular myoid cells. ET-1, known to be
produced in the seminiferous epithelium by Sertoli
cells, is derived from the inactive intermediate big endothelin-1 (big ET-1) through a specific cleavage operated by the endothelin-converting enzyme (ECE), a
membrane-bound metalloprotease with ectoenzymatic activity. The data presented suggest that the timing of
seminiferous tubule contractility is controlled locally by
the cyclic interplay between different cell types. We
have studied the expression of ECE by Sertoli cells and
used myoid cell cultures and seminiferous tubule explants to monitor the biological activity of the enzymatic reaction product. Northern blot analysis showed
that ECE-1 (and not ECE-2) is specifically expressed in
Sertoli cells; competitive enzyme immunoassay of ET
production showed that Sertoli cell monolayers are capable of cleaving big ET-1, an activity inhibited by the ECE inhibitor phosphoramidon. Microfluorimetric
analysis of intracellular calcium mobilization in single
cells showed that myoid cells do not respond to big endothelin, nor to Sertoli cell plain medium, but to the
medium conditioned by Sertoli cells in the presence of
big ET-1, resulting in cell contraction and desensitization to further ET-1 stimulation; in situ hybridization
analysis shows regional differences in ECE expression,
suggesting that pulsatile production of endothelin by
Sertoli cells (at specific "stages" of the seminiferous epithelium) may regulate the cyclicity of tubular contraction; when viewed in a scanning electron microscope, segments of seminiferous tubules containing the specific stages characterized by high expression of ECE
were observed to contract in response to big ET-1,
whereas stages with low ECE expression remained virtually unaffected. These data indicate that endothelin-mediated spatiotemporal control of rhythmic tubular
contractility might be operated by Sertoli cells through
the cyclic expression of ECE-1, which is, in turn, dependent upon the timing of spermatogenesis.
Howard
Hughes Medical Institute and Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas,
Texas 75235
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