PARENT SESSION

(19) ABSENCE OF THE DNA/RNA-BINDING PROTEIN MSY2 RESULTS IN MALE AND FEMALE INFERTILITY.

Yang, Juxiang¹, Medvedev, Sergey¹, Yu, Junying¹, Tang, Linda², Agno, Julio², Matzuk, Martin², Schultz, Richard¹, Hecht, Norman¹, ¹ University of Pennsylvania, Philadelphia, PA² Baylor College of Medicine, Houston, TX

ABSTRACT- MSY2, a germ-cell specific member of the Y-box family of DNA/RNA-binding proteins, is proposed to function as a co-activator of transcription in the nucleus and to stabilize and store maternal and paternal mRNAs in the cytoplasm. To define better its functions, we generated Msy2 null mice by the disruption of Msy2 gene with homologous recombination. In mice lacking MSY2, a normal Mendelian ratio is observed following matings between heterozygotes with equal numbers of phenotypically normal but sterile, male and female homozygotes. Spermatogenesis is disrupted in post-meiotic null germ cells with many misshapen and multinucleated spermatids, with an arrest of spermatid differentiation at step 12. No spermatozoa are detected in the epididymides of Msy2 null mice. Apoptosis is increased in the testes of homozygotes and most of the TUNEL positive cells are in meiotic prophase with a smaller number of later stage germ cell types. Real Time RT-PCR assays reveal large reductions in mRNA levels of post-meiotic male germ cell mRNAs (such as Prm1, Prm2, Tnp1, Tnp2, Akap4, and Act) and smaller reductions of meiotic germ cell transcripts (such as Acr, Ldh3, Msy4, Tsn, Tsnax and Ace). In females, there is no apparent decrease in either the number of follicles or their morphology in ovaries obtained from 2- and 8-day old Msy2-/- mice. In contrast, follicle number and progression are reduced in 21-day old Msy2-/- ovaries. In adult Msy2-/- females, oocyte loss increases, anovulation is observed, and multiple oocyte and follicle defects are seen. We conclude that MSY2 protein is required for normal spermatogenesis and oogenesis, and Msy2 represents one of a small number of germ cell-specific genes whose deletion leads to both male and female infertility. This work was supported by NIH grants HD44449 (to RMS and NBH) and HD42500 (to MMM).

KEY WORDS: DNA-binding protein, RNA-binding protein, infertility, translational control