LAUSR

Infertility affects 10% - 15% of families worldwide. However, the pathogenesis of female infertility caused by abnormal early embryonic development is not clear. A resent study showed that PABPN1L recruited BTG4 to mRNA 3'-poly(A) tails and was essential for maternal mRNA degradation. Here, we generated an PABPN1L-antibody and found "ring-like" PABPN1L aggregates in the cytoplasm of MII oocytes. PABPN1L-EGFP proteins spontaneously formed"ring-like" aggregates in vitro. This phenomenon is similar with CCR4-NOT catalytic subunit, CNOT7, when it starts deadenylation process in vitro. We constructed two mouse model (Pabpn1l  -/- and Pabpn1l  tm1a/tm1a) simulating the intron1-exon2 abnormality of human PABPN1L and found that the female was sterile and the male was fertile. Using RNA-Seq, we observed a large-scale up-regulation of RNA in zygotes derived from Pabpn1l-/- MII oocytes. We found that 9222 genes were up-regulated instead of being degraded in the Pabpn1l-♀/+♂zygote. Both the Btg4 and Cnot61 genes are necessary for the deadenylation process and Pabpn1l  -/- resembled both the Btg4 and Cnot6l knockouts, where 71.2% genes stabilized in the Btg4-♀/+♂ zygote and 84.2% genes stabilized in the Cnot6l-♀/+♂zygote were also stabilized in Pabpn1l-♀/+♂ zygote. BTG4/CNOT7/CNOT6L was partially co-located with PABPN1L in MII oocytes. The above results suggest that PABPN1L is widely associated with CCR4-NOT-mediated maternal mRNA degradation and PABPN1L variants on intron1-exon2 could be a genetic marker of female infertility. Summary sentence. "Ring-like" PABPN1L aggregates was found in the cytoplasm of MII oocytes and in vitro; intron1-exon2 abnormality of Pabpn1l leads female sterile in mice.