Connecting Cis-elements and Trans-factors with Mechanisms of Developmental Regulation of MRNA Translation in Meiotic and Haploid Mammalian Spermatogenic Cells

mRNA-specific regulation of translational activity plays major roles in directing the development of meiotic and haploid spermatogenic cells in mammals. Although many RNA-binding proteins (RBPs) have been implicated in normal translational control and sperm development, little is known about the keystone of the mechanisms: the interactions of RBPs and microRNAs with cis-elements in mRNA targets. The problems in connecting factors and elements with translational control originate in the enormous complexity of post-transcriptional regulation in mammalian cells. This creates confusion as to whether factors have direct or indirect and large or small effects on the translation of specific mRNAs. This review argues that gene knockouts, heterologous systems, and overexpression of factors cannot provide convincing answers to these questions. As a result, the mechanisms involving well-studied mRNAs (Ddx4/Mvh, Prm1, Prm2, and Sycp3) and factors (DICER1, CPEB1, DAZL, DDX4/MVH, DDX25/GRTH, translin, and ELAV1/HuR) are incompletely understood. By comparison, mutations in elements can be used to define the importance of specific pathways in regulating individual mRNAs. However, few elements have been studied, because the only reliable system to analyze mutations in elements, transgenic mice, is considered impractical. This review describes advances that may facilitate identification of the direct targets of RBPs and analysis of mutations in cis-elements. The importance of upstream reading frames in the developmental regulation of mRNA translation in spermatogenic cells is also documented.