The RNA-Binding Protein, ZFP36L2, Influences Ovulation and Oocyte Maturation

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.

CNOT 6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte

“…ZFP36L2 (zinc finger protein 36‐like 2) is a murine homolog of Xenopus C3H‐4. A natural mutation of Zfp36l2 in mice that the N‐terminal 29 amino acid residues were deleted led to oocyte maturation and ovulation defects (Ball et al , ). A new study published during the submission of our paper further demonstrated that oocyte‐specific loss of Zfp36l2 causes oocyte maturation and fertilization defects by preventing global transcriptional silencing in GV oocytes (Dumdie et al , ).…”

Single cell transcriptome profiling revealed differences in gene expression during oocyte maturation in Haimen white goats

“…Maturation of mammalian oocytes is a complex physiological process involving a large number of regulatory factors, cell structures, and different signaling pathways (Ball et al, 2014;Dang-Nguyen et al, 2014;Prunskaite-Hyyryläinen et al, 2014). For example, the cyclic adenosine monophosphate (cAMP) signaling pathway is necessary for maintaining meiosis, whereas the MAPK signaling pathway plays an important role in meiosis initiation, spindle assembly, and M2 arrest.…”

An Ancient Family of RNA-Binding Proteins: Still Important!

“…These mice appeared normal but had complete female infertility, resulting in embryonic failure at approximately the two-cell stage. Further studies with these mutant mice suggested that ZFP36L2 could bind directly to the mRNA encoding luteinizing hormone receptor (LHR), which is necessary for hormonal functioning during reproduction [50]. …”