Role of retinoid signaling in the regulation of spermatogenesis

Abstract

While the need for vitamin A for the normal progression of male germ cell differentiation has been known for many years, the molecular mechanisms underlying this requirement are poorly understood. This review will explore the aspects of the effects on spermatogenesis of dietary deprivation of vitamin A, in particular as to how they compare to the male sterility that results from the genetic ablation of function of the retinoid receptor RARalpha. The effects of other genes involved with retinoid synthesis, transport, and degradation are also considered. The possible cellular mechanisms that may be affected by the lack of retinoid signaling are discussed, in particular, cell cycle regulation and cell-cell interaction, both of which are critical for normal spermatogenesis.

Fig. 1

Vitamin A delivery and its metabolic activation to retinoic acid. RBP, retinol-binding protein; TTR, transthyretin; CRBP-I, cellular retinol-binding protein, type I; CRABP-I, cellular retinoic acid-binding protein, type I; CRABP-II, cellular retinoic acid-binding protein, type II; ADH, medium-chain alcohol dehydrogenases; RolDH, short-chain alcohol dehydrogenase or short-chain dehydrogenase/reductase; RALDH, retinal dehydrogenase; LRAT, lecithin:retinol acyltransferase; REH, retinyl ester hydrolase. Adapted from Gottesman et al. (2001).

Fig. 2

Proposed retinoid metabolism, transport, and action in the seminiferous tubules of testis. Circulating retinol (Rol) is bound to RBP and complexed with TTR. It is then internalized in the peritubular myoid cells and then passes to Sertoli cells and spermatogenic cells outside the blood-testis barrier. CRBP-I is present in Sertoli cells and may facilitate retinol update from circulating retinol-RBP complexes. Rol-CRBP in Sertoli cells then oxidizes to retinal by ADH in Sertoli cells or certain spermatogenic cells (see section V). By unknown processes, Ral is transferred to spermatogenic cells. Then, RALDH1 or RALDH2 in various spermatogenic cells (SG, early meiotic spermatocytes, PS, RS) oxidizes retinal to retinoic acid; however, neither RALDH1 nor RALDH2 has been found in Sertoli or peritubular myoid cells. Alternatively, the retinol will convert to retinyl esters for storage. CRABP-I is found in the cytoplasm of spermatogenic cells where it may sequester retinoic acid in the cytoplasm and prevent ligand-dependent activation of the nuclear retinoid receptor. Accordingly, inside the blood-testis barrier, no CRABP-I was found in any cells. CRABP-II, is however, found in Sertoli cells. The expression of degrading enzymes is not well described, but is basically characterized as “being expressed in the testis”. Similar pathways of uptake and metabolism are believed to function in Leydig cells as in Sertoli cells. RBP, retinol-binding protein; TTR, transthyretin; CRBP-I, cellular retinol-binding protein, type I; CRABP-I, cellular retinoic acid-binding protein, type I; CRABP-II, cellular retinoic acid-binding protein, type I; ADH, medium-chain alcohol dehydrogenases; RolDH, short-chain alcohol dehydrogenase or short-chain dehydrogenase/reductase; RALDH, retinal dehydrogenase; LRAT, lecithin:retinol acyltransferase; REH, retinyl ester hydrolase. PL/SG, preleptotene spermatocytes or spermatogonia; L/Z, leptotene/zygotene spermatocytes; PS, pachytene spermatocytes; RS, round spermatids; TJ, tight junction, Sertoli cell barrier. Adapted from Livera et al. (2002) and Kim and Akmal (1996).