Liver-Specific Deletion of Cnot11 Delays Postnatal Hepatocyte Maturation and Transiently Impairs Liver Function in Mice.

The CCR4-NOT complex is a central regulator of post-transcriptional gene expression that controls mRNA deadenylation and decay. Although the catalytic subunits have been well characterized, the physiological roles of several non-catalytic subunits including CNOT11 in mammalian tissues remain incompletely understood. Here, we investigate the physiological role of CNOT11 using genetic mouse models. No homozygous global Cnot11 knockout mice are obtained from heterozygous intercrosses, indicating that CNOT11 is required for early development. We generate hepatocyte-specific Cnot11 knockout mice (Cnot11-LKO) and find that Cnot11-LKO mice exhibit growth retardation and alterations in serum biochemical parameters during early postnatal stages, which are largely resolved by adulthood. Histological analysis does not reveal overt liver injury, while morphological differences in hepatocytes are observed. A marked increase in Ki67-positive cells was observed in the liver of Cnot11-LKO mice relative to control mice. Most Ki67-positive cells express HNF4A, suggesting that hepatocyte maturation is still in progress in the absence of CNOT11. Transcriptomic analyses of early postnatal livers reveal increased expression of cell cycle-related genes and reduced expression of metabolic genes, further supporting delayed liver maturation. These findings suggest that CNOT11 contributes to proper postnatal liver maturation and is required for the timely establishment of metabolically mature hepatocyte functions.