RRC ID 59674
Author Suzuki T, Kikuguchi C, Nishijima S, Nagashima T, Takahashi A, Okada M, Yamamoto T.
Title Postnatal liver functional maturation requires Cnot complex-mediated decay of mRNAs encoding cell cycle and immature liver genes.
Journal Development
Abstract Liver development involves dramatic gene expression changes mediated by transcriptional and post-transcriptional control. Here, we show that the Cnot deadenylase complex plays a crucial role in liver functional maturation. The Cnot3 gene encodes an essential subunit of the Cnot complex. Mice lacking Cnot3 in liver have reduced body and liver masses, and they display anemia and severe liver damage. Histological analyses indicate that Cnot3-deficient (Cnot3-/- ) hepatocytes are irregular in size and morphology, resulting in formation of abnormal sinusoids. We observe hepatocyte death, increased abundance of mitotic and mononucleate hepatocytes, and inflammation. Cnot3-/- livers show increased expression of immune response-related, cell cycle-regulating and immature liver genes, while many genes relevant to liver functions, such as oxidation-reduction, lipid metabolism and mitochondrial function, decrease, indicating impaired liver functional maturation. Highly expressed mRNAs possess elongated poly(A) tails and are stabilized in Cnot3-/- livers, concomitant with an increase of the proteins they encode. In contrast, transcription of liver function-related mRNAs was lower in Cnot3-/- livers. We detect efficient suppression of Cnot3 protein postnatally, demonstrating the crucial contribution of mRNA decay to postnatal liver functional maturation.
Volume 146(4)
Published 2019-2-15
DOI 10.1242/dev.168146
PII dev.168146
PMID 30733279
PMC PMC6398447
MeSH Albumins / metabolism Anemia / metabolism Animals Animals, Newborn Apoptosis Bile Ducts / metabolism Cell Cycle Female Gene Expression Profiling Gene Expression Regulation, Developmental* Hepatocytes / cytology Hepatocytes / metabolism Inflammation Lipids / chemistry Liver / embryology Liver / growth & development* Liver / metabolism Male Mice Mice, Knockout Promoter Regions, Genetic RNA, Messenger / metabolism Time Factors Transcription Factors / genetics Transcription Factors / metabolism*
IF 5.763
Times Cited 5
Human and Animal Cells Hepa 1-6(RCB1638)