Retinoid signaling during spermatogenesis as revealed by genetic and metabolic manipulations of retinoic acid receptor alpha

Abstract

The importance of dietary retinol (vitamin A) and retinoid signaling for normal development and differentiation has been recognised for many years. Vitamin A deficiency results in a variety of abnormalities, most of which can be corrected by supplementing the diet with all-trans-retinoic acid (ATRA), with the exception of blindness and male sterility. ATRA, an active metabolite of vitamin A, functions primarily by binding to nuclear receptors of the steroid hormone superfamily, the retinoic acid receptors (RARs). Gene targeting studies revealed the importance of ATRA signaling through the RARs for spermatogenesis. Mice that are homozygous for a null mutation in the gene encoding RARalpha, Rara-/-, exhibit defects in spermatogenesis and male sterility. The abnormalities in these RARalpha-deficient testes have been examined in detail in a series of recent studies from our laboratory and will be summarised in this paper. We also review how dietary, pharmacologic and genetic strategies, alone or in combination, can be used to gain further insight into retinoid function in mammalian spermatogenesis.

Fig. 1

Retention of spermatids, failure of spermatid release and aberrant orientation of spermatids of Rara^−/− testis observed at stage XI within the seminiferous epithelium. The acrosome of spermatids at stage IX in histological sections of testes from RARα^+/+ (A) and RARα^−/− males (B) was detected with PAS staining (magenta color). P, pachytene spermatocytes; PL/L, preleptotene or leptotene spermatocytes; Arabic numerals, the step of elongated spermatids. Roman numerals indicate the stage of the seminiferous tubule. A–B, 60×. Arrows in A–B indicate the orientation of elongated spermatids while the bracket in B indicates retentions of spermatids.

Fig. 2

Diagrammatic representation of the spermatogenic cycle illustrating the profound abnormalities in RARa-deficient mice clustered in stage VIII–IX tubules. Details of the symbols used in the staging map shown can be found in Russell et al. (Russell et al., 1990). The green bar line indicates the particular stage, stage VIII, that showed the highest frequency of cellular abnormalities. Red arrows point to the specific cell type at stage VIII, where various abnormalities were found.