Paracrine mechanisms involved in the control of early stages of Mammalian spermatogenesis

Abstract

Within the testis, Sertoli-cell is the primary target of pituitary FSH. Several growth factors have been described to be produced specifically by Sertoli cells and modulate male germ cell development through paracrine mechanisms. Some have been shown to act directly on spermatogonia such as GDNF, which acts on self-renewal of spermatogonial stem cells (SSCs) while inhibiting their differentiation; BMP4, which has both a proliferative and differentiative effect on these cells, and KIT ligand (KL), which stimulates the KIT tyrosine-kinase receptor expressed by differentiating spermatogonia (but not by SSCs). KL not only controls the proliferative cycles of KIT-positive spermatogonia, but it also stimulates the expression of genes that are specific of the early phases of meiosis, whereas the expression of typical spermatogonial markers is down-regulated. On the contrary, FGF9 acts as a meiotic inhibiting substance both in fetal gonocytes and in post-natal spermatogonia through the induction of the RNA-binding protein NANOS2. Vitamin A, which is metabolized to Retinoic Acid in Sertoli cells, controls both SSCs differentiation through KIT induction and NANOS2 inhibition, and meiotic entry of differentiating spermatogonia through STRA8 upregulation.

Keywords: gene expression; growth factors; meiosis; paracrine control; primordial germ cells; signal transduction; spermatogenesis; spermatogonial stem cells.

Figure 1

Sertoli-cell controlled paracrine mechanisms acting on the early stages of mammalian spermatogenesis. Paracrine factors secreted by Sertoli cells (whose membrane is represented by dashed circles) are enclosed within solid line circles. Follicle stimulating hormone (FSH) is enclosed within a solid line square. Endogenous factors expressed by germ cells are represented by non-enclosed words. Blue colors refer to paracrine and endogenous factors that promote self-renewal of spermatogonial stem cells (SSCs) and inhibit spermatogonial differentiation and/or meiotic entry. Red colors refer to paracrine and endogenous factors that promote spermatogonial differentiation. Purple colors refer to endogenous factors which promote spermatogonial differentiation but at the same time inhibit meiotic entry. Green colors refer to endogenous factors that drive entry into meiosis. Lines delimited by small ellipsoids refer to the stage of expression of the germ cell endogenous factors involved in either self-renewal of SSCs and inhibition of differentiation (blue colors) or in differentiation (red colors) and meiotic entry (green colors). The succession of the various types of germ cells during the earliest stages of mouse spermatogenesis is represented in the center of the image: As, a single spermatogonia; Apr, a paired spermatogonia; Aal, a aligned spermatogonia; A1, A2, A3, A4, type A1–A4 spermatogonia; Int, intermediate spermatogonia; B, type B spermatogonia; PL, pre-leptotene spermatocytes.