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

Abstract

Infertility affects 10-15% of families worldwide. 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-♀/+♂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-♀/+♂ 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 intron 1-exon 2 could be a genetic marker of female infertility.

• Authors: Ying Wang, Tianhao Feng, Mingcong Zhu, Xiaodan Shi, Zerui Wang, Siyu Liu, Xin Zhang, Jintao Zhang, Shuqin Zhao, Junqiang Zhang, Xiufeng Ling, Mingxi Liu
• Journal: Biology of reproduction (Biol Reprod) Vol. 106 Issue 1 Pg. 83-94 (01 13 2022) ISSN: 1529-7268 [Electronic] United States
• PMID: 34726234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Btg4 protein, mouse
• Ccr4 protein, mouse
• Cell Cycle Proteins
• PABPN1 protein, mouse
• PABPN1L protein, human
• Poly(A)-Binding Protein I
• Poly(A)-Binding Proteins
• Protein Aggregates
• RNA, Messenger
• Receptors, CCR4
• enhanced green fluorescent protein
• Green Fluorescent Proteins

Topics

• Animals
• Cell Cycle Proteins (genetics, physiology)
• Cytoplasm (chemistry)
• Female
• Gene Expression Regulation, Developmental (physiology)
• Green Fluorescent Proteins (chemistry)
• Humans
• Infertility, Female
• Male
• Mice
• Mice, Knockout
• Oocytes (ultrastructure)
• Poly(A)-Binding Protein I (chemistry, genetics, physiology)
• Poly(A)-Binding Proteins (chemistry, genetics)
• Protein Aggregates
• RNA, Messenger (metabolism)
• Receptors, CCR4 (genetics, physiology)
• Zygote (metabolism)