Absence of the DNA-/RNA-binding protein MSY2 results in male and female infertility

Abstract

MSY2, a germ-cell-specific member of the Y-box family of DNA-͞ RNA-binding proteins, is proposed to function as a coactivator of transcription in the nucleus and to stabilize and store maternal and paternal mRNAs in the cytoplasm. In mice lacking Msy2, a normal Mendelian ratio is observed after matings between heterozygotes with equal numbers of phenotypically normal but sterile male and female homozygotes (Msy2 ؊/؊ ). Spermatogenesis is disrupted in postmeiotic null germ cells with many misshapen and multinucleated spermatids, and no spermatozoa are detected in the epididymis. Apoptosis is increased in the testes of homozygotes, and real-time RT-PCR assays reveal large reductions in the mRNA levels of postmeiotic male germ cell mRNAs and smaller reductions of meiotic germ cell transcripts. 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. Thus, Msy2 represents one of a small number of germ-cell-specific genes whose deletion leads to the disruption of both spermatogenesis and oogenesis.he highly conserved family of Y-box proteins, expressed in organisms ranging from bacteria to humans, contains a cold-shock domain essential for nucleic-acid binding and variable N and C termini that confer binding specificity (1). As DNA-binding proteins, Y-box proteins serve as transcription coactivators, recognizing DNA motifs such as CTGATTGGC͞ TC͞TAA (2). As RNA-binding proteins, Y-box proteins help stabilize mRNAs and, depending on their concentration, can inhibit or stimulate mRNA translation (3, 4).Among DNA-͞RNA-binding proteins, the mouse Y-box protein MSY2 is one of the most abundant, constituting 0.7% ( Fig. 1) and 2% of total protein in male germ cells and fully grown oocytes, respectively (5, 6). MSY2 is the mouse ortholog of the Xenopus laevis FRGY2 (2) and human Contrin proteins (7), Y-box proteins proposed to be solely expressed in germ cells (8). In the testis, Msy2 is expressed in meiotic and postmeiotic germ cells, where it is believed to function in long-term mRNA storage and stabilization because cessation of transcription in postmeiotic germ cells necessitates posttranscriptional regulation for many mRNAs encoding late-stage germ cell and spermatozoan proteins (8). In addition, MSY2 marks specific mRNAs in the nucleus for storage in the cytoplasm, providing a linkage between transcription and mRNA storage for a subset of male germ cell mRNAs (9).In the female, MSY2 protein accumulates during oocyte growth, but after fertilization, it is totally degraded by the late two-cell stage (6). As in postmeiotic male germ cells, MSY2 is located in the cytoplasm in oocytes, but, in contrast to male germ cells, where MSY2 is soluble, Ϸ70% of MSY2 is retained after permeabilization procedures that release Ͼ70...

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

“…Handel described a large-scale joint initiative involving The Jackson Laboratory and Cornell University for the discovery of genes required for meiosis and fertility in mice [Yang et al, 2005;Handel et al, 2006]. Gene mutations were generated by treating male mice with ENU and screening the progeny of G2 backcrosses for infertility.…”

Expression profiling reveals meiotic male germ cell mRNAs that are translationally up- and down-regulated

“…Raw count values obtained with SDS 2.0 (Applied Biosystems) were imported into EXCEL (Microsoft) to calculate the fold changes normalized against Gapdh as described in ref. 56.…”

GDNF Signaling Regulates YBX1/mRNA Interactions in Mouse Spermatogonia.

“…Because YBX1 is regulating the translation of genes that are known to be important for spermatogenesis (such as DAZL and PLZF), we predict that this protein is critical to normal SSC function. While we cannot discount the possibility that YBX1 is redundant in function, there is significance that another Y-box protein, MSY2, is only expressed in later spermatogenic cells and is necessary for spermatogenesis because of its function in translational regulation [210,223,224]. It occurs to us that YBX1 and MSY2 may be performing similar functions in different cells.…”

“…A YBX1 homologue, MSY2, is expressed in differentiating germ cells. MSY2 is involved in RNA stability, and when it is knocked out, mice are viable but males and females are infertile, giving us further evidence for the importance of the Y box family of proteins in spermatogenesis [210,211].…”