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. 2005 Apr 19;102(16):5755-60.
doi: 10.1073/pnas.0408718102. Epub 2005 Apr 11.

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

Juxiang Yang  1 , Sergey Medvedev, Junying Yu, Linda C Tang, Julio E Agno, Martin M Matzuk, Richard M Schultz, Norman B Hecht
Affiliations

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

Juxiang Yang et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Fig. 1.
Fig. 1.
Strategy for targeted disruption of the Msy2 gene. (A) Exons are represented by vertical bars, and introns are represented by intervening horizontal lines. Exons 1, 2, 2′, and 3 and flanking region were replaced by homologous recombination with a hypoxanthine phosphoribosyl transferase (Hprt) gene driven by the Pgk promoter. Restriction sites: A, ApaI; B, BamHI; RI, EcoRI; RV, EcoRV; Xb, XbaI; and Xm, XmaI. (B) Southern blot genotyping of DNA from wild-type, heterozygous, and homozygous mice. The mice were genotyped by Southern blot analysis of purified tail DNA digested with EcoRI and BamHI and hybridized with a probe 5′ to the disrupted gene. A 5.9-kb DNA band was seen in targeted mice replacing the 9.3-kb DNA fragment of wild-type mice.
Fig. 2.
Fig. 2.
Msy2 mRNA is absent in the testes of Msy2–/– mice. (A) Northern blot of total testis RNA (10 μg) from wild-type, heterozygous, and homozygous mice hybridized with probes for Msy2, clusterin, actin, Tnp2, and Prm2. (B) Immunoblot of testes extracts (5 μg for MSY2 and 20 μg for clusterin and actin) were probed with anti-MSY2, anti-clusterin, and anti-actin. (C) Immunoblot of extracts (5 μg) of brain (lane 1), pachytene spermatocytes (lane 2), round spermatids (lane 3), and a mixed population of dissociated male germ cells (lane 4). (D) Immunoblot obtained with 25 (lane 1) wild-type oocytes, 25 heterozygote oocytes (lane 2), and 25 Msy2-null oocytes (lane 3). The oocytes were transferred to sample buffer that was then directly applied to the gel, thus ensuring no loss of protein in the samples.
Fig. 3.
Fig. 3.
Histology of testes and epididymis from 6- and 7-week-old wild-type and Msy2-null mice. (A and B) Msy2–/– testis. (C) Msy2+/+ testis. (D) Msy2–/– testis. (E) Msy2+/+ epididymis. (F) Msy2–/– epididymis. (Scale bars: A, E, and F, 20 μm; B–D, 80 μm.)
Fig. 4.
Fig. 4.
TUNEL assay of testes from wild-type and Msy2-null mice. Apoptotic cells (brown) were detected by in situ TUNEL peroxidase staining in testis sections from wild-type mice. (Scale bars: A and B, 20 μm; C and D, 100 μm.)
Fig. 5.
Fig. 5.
Histology of ovaries of Msy2-null and control mice. (A–C) Three-week-old wild-type (A), Msy2+/– (B), and Msy2–/– (C) ovaries captured at the same magnification. (D) Wild-type 8-week-old ovary. (E–I) Msy2–/– ovaries at 8 weeks (E), 20 weeks (F and G), and 8 months (H and I). Note the numerous follicles in A and B compared with C. Note the numerous corpora lutea (CL) and follicles at various stages of development in D and the absence of corpora lutea, reduced number of follicles, hemorrhagic cyst (HC), and increased interstitial tissue in E. (Scale bars: 100 μm.)
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