Cycles, waves, and pulses: Retinoic acid and the organization of spermatogenesis

BACKGROUND: Spermatogenesis in mammals is organized in a manner that maximizes sperm production. The central aspect of this organization is the cycle of the seminiferous epithelium that is characterized by an asynchronous repeating series of germ cell associations. These cell associations are the result of a fixed point of entry into the cycle at regular short time intervals and the longer time required for cells to fully differentiate and exit the cycle. OBJECTIVE: This review will examine the current information on the action and metabolism of retinoic acid in the testis, the interaction of retinoic acid (RA) with the cycle and the spermatogenic wave, and the mechanisms that can lead to synchronous spermatogenesis. Finally, the unique applications of synchronous spermatogenesis to the study of the cycle and the mass isolation of specific germ cell populations are described. MATERIALS AND METHODS: Retinoic acid metabolism and spermatogonial differentiation have been examined by gene deletions, immunocytochemistry, chemical inhibitors, and mass spectrometry. RESULTS, DISCUSSION, AND CONCLUSION: Both the Sertoli cells and the germ cells have the capacity to synthesize retinoic acid from retinol and in the mouse the entry into the cycle of the seminiferous epithelium, and the subsequent conversion of undifferentiated spermatogonia into differentiating spermatogonia is governed by a peak of RA synthesis occurring at stages VIII‐IX of the cycle. Normal asynchronous spermatogenesis can be modified by altering RA levels, and as a result the entire testis will consist of a few closely related stages of the cycle.