@phdthesis{oai:oist.repo.nii.ac.jp:00001533,
 author = {Sarmah, Hemanta},
 month = {2020-06-01, 2020-06-01},
 note = {Messenger RNA (mRNA) decay is an indisputable component of gene expression regulation. In higher eukaryotes such as humans and mice, this process is mainly governed by a multi-subunit protein assemblage known as the CCR4-NOT complex. The complex is composed of a central scaffold CNOT1, regulatory subunits CNOT2 and CNOT3, a catalytic core consisting of CNOT6, CNOT6L, CNOT7, and CNOT8 proteins, and additional three subunits CNOT9, CNOT10, and CNOT11. In this study, I analyzed the role of subunit CNOT9 in target mRNA decay in the context of mouse embryonic development. CNOT9 knockout mice appear normal during onset of gastrulation, yet exhibit severe growth and differentiation defects during mid-late gastrulation stages (E8.5 to E9.5), accompanied by extensive cell death. Similar nature of phenotype was also observed in epiblast speci<br />fic CNOT9 deletion mutants, suggesting major contribution of epiblast lineage cells in determining knockout embryo phenotype. At the molecular level, CNOT9 is primarily localized within the cytoplasm and bridges interactions between the CCR4-NOT complex and the miRNA-RISC complex. Transcriptomic analysis identi<br />ed key determinants of gastrulation such as Nodal, Lefty1/2, Cfc-1 to be signi<br />cantly upregulated in CNOT9 KO embryos relative to controls. Among these targets, Lefty2 mRNA expression was found to be post-transcriptionally regulated by CNOT9. Reporter mRNA containing Lefty2 3'-UTR element had higher stability in cells expressing CNOT1-binding-mutant form of CNOT9, compared to cells expressing wild-type CNOT9. Finally, in-vitro experiments with CNOT9 KO embryonic stem (ES) cells further substantiated the importance of gastrulation regulation via CNOT9.},
 school = {Okinawa Institute of Science and Technology Graduate University},
 title = {哺乳類CCR4-NOT複合体成分 CNOT９の分子生物学的・生理学的機能},
 year = {}
}