RETINOIC ACID SYNTHESIS AND DEGRADATION: IMPLICATIONS FOR PROPER GERM CELL DEVELOPMENT
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Spermatogenesis is absolutely essential for mammalian reproduction. This highly organized and tightly controlled process is regulated, in part, by retinoic acid (RA). This essential molecule plays key roles in many aspects of spermatogenesis, namely spermatogonial differentiation, blood-testis barrier (BTB) reorganization, meiotic initiation, and spermiation. While the importance of RA is well known, the regulation of this molecule has not been well studied. RA availability is directly influenced by its synthesis and degradation, metabolized by the ALDH and CYP26 families respectively. It has recently been published that RA is present in a pulsatile manner across the spermatogenic cycle, but it is not known if these enzyme families play a role in this stage-specific availability of RA. The data presented here provides strong evidence that neither the ALDHs nor the CYP26s are regulated in a cyclic manner, suggesting that the availability of retinaldehyde, the precursor of RA, is responsible of the observed pulsatility. In addition to investigating the stage-specificity of the ALDH and CYP26 enzymes, specific inhibitors were used to investigate the effects on spermatogenesis in a high and low testicular RA environment. The data presented here shows that CYP26 inhibition causes precocious spermatogonial differentiation in the adult mouse and is able to drive synchronous spermatogenesis in the neonatal mouse. Additionally, both low and high testicular RA environments had abnormal effects on Sertoli cells. After inhibiting RA synthesis, BTB permeability was shown to be increased. Conversely, neonatal animals treated with exogenous RA were shown to have reduced Sertoli cell number, possibly due to premature cessation of proliferation. Finally, meiotic recombination was shown to be increased and decreased in a low and high testicular RA environment, respectively. These data highlight the importance of proper RA homeostasis within the testis, and illuminate some of the consequences of abnormal RA levels. Taken all together, the data presented in this work show the importance of understanding the expression and function of the ALDH and CYP26 enzymes in the mammalian testis.