PABPN1L assemble into "ring-like" aggregates in the cytoplasm of MII oocytes and is associated with female infertility

Infertility affects 10-15% of familiesworldwide. However, the pathogenesis of female infertility caused by abnormal early embryonic development is not clear. A recent study showed that poly(A)binding protein nuclear 1-like (PABPN1L) recruited BTG anti-proliferation factor 4 (BTG4) to mRNA 3'-poly(A) tails and was essential for maternal mRNA degradation. Here, we generated a 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, CCR4-NOT transcription complex subunit 7 (CNOT7), when it starts deadenylation process in vitro. We constructed two mouse model (Pabpn1l(-/-) and Pabpn1l(tm1a/tm1a)) simulating the intron 1-exon 2 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(-female/+male) zygote. Both the Btg4 and CCR4-NOT transcription complex subunit 6 like (Cnot6l) genes are necessary for the deadenylation process and Pabpn1l(-/-) resembled both the Btg4 and Cnot6l knockouts, where 71.2% genes stabilized in the Btg4(-female/+male) zygote and 84.2% genes stabilized in the Cnot6l(-female/+male) zygote were also stabilized in Pabpn1l(-female/+male). 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 intron 1-exon 2 could be a genetic marker of female infertility. Summary sentence "Ring-like" PABPN1L aggregates were found in the cytoplasm of MII oocytes and in vitro; intron 1-exon 2 abnormality of Pabpn1l leads female sterile in mice.