Regulation of mammalian spermatogenesis by miRNAs

Abstract

Male fertility requires the continual production of sperm by the process of spermatogenesis. This process requires the correct timing of regulatory signals to germ cells during each phase of their development. MicroRNAs (miRNAs) in germ cells and supporting Sertoli cells respond to regulatory signals and cause down- or upregulation of mRNAs and proteins required to produce proteins that act in various pathways to support spermatogenesis. The targets and functional consequences of altered miRNA expression in undifferentiated and differentiating spermatogonia, spermatocytes, spermatids and Sertoli cells are discussed. Mechanisms are reviewed by which miRNAs contribute to decisions that promote spermatogonia stem cell self-renewal versus differentiation, entry into and progression through meiosis, differentiation of spermatids, as well as the regulation of Sertoli cell proliferation and differentiation. Also discussed are miRNA actions providing the very first signals for the differentiation of spermatogonia stem cells in a non-human primate model of puberty initiation.

Keywords: DICER; Maturation arrest; Retinoic acid; Self-renewal; Spermatogonia stem cell.

Figure 1.. Regulatory miRNAs expressed in germ cells and Sertoli cells.

(A) miRNAs promoting (arrows) spermatogonia stem cell (SSC) renewal that are regulated by retinoic acid (black box), the GDNF pathway (green box) or other pathways (red box) are listed. Let-7 and miR-135 are denoted as inhibiting stem cell renewal. Additional miRNAs are shown to promote (arrows) or inhibit (blocking symbol) the process of spermatogonia differentiation, maturation to become spermatocytes, meiosis and chromatin compaction in spermatids (RA, retinoic acid). (B) Regulatory miRNAs expressed in Sertoli cells that alter Sertoli cell proliferation, respond to hormone stimulation or regulate the support of germ cells are listed.

Figure 2.. Gonadotropin treatment induces AR expression in the juvenile monkey.

Immunofluorescence analysis of AR expression (green staining) in sections of juvenile mouse testis infused with vehicle (VEH) or gonadotropins for 48 or 96 h. AR immunoreactivity is denoted in Sertoli cells (circles), peritubular myoid cells (arrows) and Leydig cells (arrowheads).