Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice

Abstract

In eukaryotes, diploid cells give rise to haploid cells via meiosis, a program of two cell divisions preceded by one round of DNA replication. Although key molecular components of the meiotic apparatus are highly conserved among eukaryotes, the mechanisms responsible for initiating the meiotic program have diverged substantially among eukaryotes. This raises a related question in animals with two distinct sexes: Within a given species, are similar or different mechanisms of meiotic initiation used in the male and female germ lines? In mammals, this question is underscored by dramatic differences in the timing of meiotic initiation in males and females. Stra8 is a vertebrate-specific, cytoplasmic factor expressed by germ cells in response to retinoic acid. We previously demonstrated that Stra8 gene function is required for meiotic initiation in mouse embryonic ovaries. Here we report that, on an inbred C57BL/6 genetic background, the same factor is also required for meiotic initiation in germ cells of juvenile mouse testes. In juvenile C57BL/6 males lacking Stra8 gene function, the early mitotic development of germ cells appears to be undisturbed. However, these cells then fail to undergo the morphological changes that define meiotic prophase, and they do not display the molecular hallmarks of meiotic chromosome cohesion, synapsis and recombination. We conclude that, in mice, Stra8 regulates meiotic initiation in both spermatogenesis and oogenesis. Taken together with previous observations, our present findings indicate that, in both the male and female germ lines, meiosis is initiated through retinoic acid induction of Stra8.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Photomicrographs of hematoxylin-stained sections from wild-type and Stra8-deficient testes at p10 or p15 (10 or 15 days after birth, respectively). Black arrows indicate representative preleptotene cells; red arrows, leptotene spermatocytes; green arrows, pachytene spermatocytes; arrowheads, apoptotic cells.

Fig. 2.

Immunohistochemical staining for γ-H2AX protein in sections of wild-type and Stra8-deficient testes 10 days after birth.

Fig. 3.

Quantitative RT-PCR analysis of Spo11 and Dmc1 mRNA levels in Stra8-heterozygous and Stra8-deficient testes, 10 or 15 days after birth. Plotted here are average fold changes, normalized to Hprt, in independent biological replicates (two replicates at p10, and four at p15). Error bars represent standard deviations among biological replicates; P values are from the Smith–Satterthwaite test, one-tailed.

Fig. 4.

Immunohistochemical staining for SYCP3 protein (A) or REC8 protein (B) in germ cells from wild-type and Stra8-deficient p15 testes. Costaining for GCNA confirms the germ-cell identity of these nuclei.

Fig. 5.

Analysis of BrdU incorporation in sections of wild-type and Stra8-deficient testes 21 days after birth. (A) Immunohistochemical staining for BrdU counterstained with hematoxylin. (B) Interpretation of images in A. On these grayscale versions of the images in A, magenta dots indicate BrdU-positive preleptotene cells, and yellow dots indicate BrdU-positive type B spermatogonia.