Abstract
ZFP36L2 protein destabilizes AU-rich element-containing transcripts and has been implicated in female fertility. In the C57BL/6NTac mouse, a mutation in Zfp36l2 that results in the decreased expression of a form of ZFP36L2 in which the 29 N-terminal amino acid residues have been deleted, ΔN-ZFP36L2, leads to fertilized eggs that arrest at the two-cell stage. Interestingly, homozygous ΔN-Zfp36l2 females in the C57BL/6NTac strain release 40% fewer eggs than the WT littermates (Ramos et al., 2004), suggesting an additional defect in ovulation and/or oocyte maturation. Curiously, the same ΔN-Zfp36l2 mutation into the SV129 strain resulted in anovulation, prompting us to investigate a potential problem in ovulation and oocyte maturation. Remarkably, only 20% of ΔN-Zfp36l2 oocytes in the 129S6/SvEvTac strain matured ex vivo, suggesting a defect on the oocyte meiotic maturation process. Treatment of ΔN-Zfp36l2 oocytes with a PKA inhibitor partially rescued the meiotic arrested oocytes. Furthermore, cAMP levels were increased in ΔN-Zfp36l2 oocytes, linking the cAMP/PKA pathway and ΔN-Zfp36l2 with meiotic arrest. Since ovulation and oocyte maturation are both triggered by LHR signaling, the downstream pathway was investigated. Adenylyl cyclase activity was increased in ΔN-Zfp36l2 ovaries only upon LH stimulation. Moreover, we discovered that ZFP36L2 interacts with the 3′UTR of LHR mRNA and that decreased expression levels of Zfp36l2 correlates with higher levels of LHR mRNA in synchronized ovaries. Furthermore, overexpression of ZFP36L2 decreases the endogenous expression of LHR mRNA in a cell line. Therefore, we propose that lack of the physiological down regulation of LHR mRNA levels by ZFP36L2 in the ovaries is associated with anovulation and oocyte meiotic arrest.
Highlights
Some perceive infertility as a quality-of-life issue, it is a disease with increasing public health concerns [1]
While the majority of WT oocytes progressed to metaphase II (MII) with condensed chromosomes (Fig.1B, upper right panel), the DN-Zfp36l2 oocytes were arrested at an immature stage with their chromosomes still dispersed in a prophase I pattern characteristic of the germinal vesicle (GV) stage (Fig.1B, lower right panel)
This observation indicated that oocytes derived from homozygous DN-Zfp36l2 females have processes involved in oocyte maturation inhibited or, alternatively, have processes involved in the maintenance of meiotic arrest potentiated
Summary
Some perceive infertility as a quality-of-life issue, it is a disease with increasing public health concerns [1]. Infertility is a global health issue affecting 10–15% of the 1.5 billion women of reproductive age [2]. The majority of these women have no access to infertility treatment, and even in developed economies there are great inequalities in access to diagnosis and treatment [3]. Using knowledge obtained by studying a genetically engineered mouse model, we propose a new molecular basis for unexplained female infertility involving the ZFP36L2 RNA-binding protein’s role in ovulation and oocyte maturation. Our results suggest that decreased ZFP36L2 expression can, conceivably, be the basis of some cases of unexplained female infertility in humans
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