Spermatogenesis Lost in Translation

Science Signaling  28 Apr 2009:
Vol. 2, Issue 68, pp. ec146
DOI: 10.1126/scisignal.268ec146

During meiotic prophase and during differentiation of spermatids, chromatin is not available for transcription. Thus, key elements in regulation of spermatogenesis in mammals occur through posttranscriptional as well as transcriptional regulation. Paronetto et al. describe an essential role for the protein Sam68 (Src-associated substrate in mitosis of 68 kD, also called KH-DRBS1) in spermatogenesis that appears to reflect its regulation of a set of particular mRNAs. Sam68 is a member of a family of RNA binding proteins called STAR (signal transduction and activation of RNA) proteins that regulate a range of processes, including RNA stability, export, and splicing and mRNA translation as well. Mice lacking Sam68 fail to produce mature spermatozoa and are thus infertile, and Paronetto explored the mechanism behind this effect. Array analysis of mRNA from testes of knockout animals identified hundreds of genes that showed increased or decreased expression as compared with similar preparations from control animals. Sam68 was found to be associated with translation initiation complexes in normal male germ cells. The authors looked more closely at two mRNAs that decreased in abundance in Sam68 knockout cells: SPDYA, a cell cycle regulator that functions in meiotic maturation, and SPAG16, which functions in the sperm axoneme and is required for motility. Although translation in general appeared not to be altered in the knockout animals, recruitment to polysomes and translation of Spag16 and Spdya mRNAs were decreased. In spermatocyes stimulated to undergo meiotic divisions, the normal accumulation of SPDYA and SPAG16 proteins was suppressed in spermatocytes from knockout animals. In a heterologous system [human embryonic kidney (HEK) 293 cells], expression of Sam68 enhanced reporter translation driven by the 3′ untranslated region of Spag16 mRNA. A mutant form of Sam68 lacking its phosphorylation site regulated by mitogen-activated protein kinase did not enhance translation. The authors propose that, through its Src and MAPK-dependent phosphorylation, Sam68 may link intracellular signaling pathways to RNA processing, in particular controlling recruitment to polysomes and enhanced translation of a set of mRNAs required for spermatogenesis.

M. P. Paronetto, V. Messina, E. Bianchi, M. Barchi, G. Vogel, C. Moretti, F. Palombi, M. Stefanini, R. Geremia, S. Richard, C. Sette, Sam68 regulates translation of target mRNAs in male germ cells, necessary for mouse spermatogenesis. J. Cell Biol. 185, 235–249 (2009). [Abstract] [Full Text]