Targeting retrovirus-derivedRtl8aand8bcauses late onset obesity and neurodevelopmental defects

Abstract

AbstractRetrotransposon Gag-like (RTL) 8A, 8B and 8C are triplet genes of uncertain function that form a cluster on the X chromosome. They are eutherian-specific genes presumably derived from a certain retrovirus. Here, we demonstrate thatRtl8aandRtl8bplay an important role in growth and behavior via brain functions in the hypothalamus and prefrontal cortex.Rtl8aandRtl8bdouble knockout (DKO) mice exhibited overgrowth due to hyperphagia from young adulthood and reduced social responses, increased apathy-like behavior. RTL8A and RTL8B proteins are localized to both the nucleus and cytoplasm of neurons presumably due to an N-terminal nuclear localization signal-like sequence. An increment in nucleus size was also detected in the neurons in the prefrontal cortex, suggesting neuronal dysfunction. These data give another strong evidence that retrovirus-derived acquired genes contributed to the establishment of the current eutherian developmental system in a wide variety of ways.Summary statementRtl8aandRtl8bdouble knockout mice exhibited late onset obesity and neurodevelopmental defects, demonstrating that these eutherian specific retrovirus-derived acquired genes encoding proteins with only 113 amino acids play important roles in the brain presumably via their functions in the hypothalamus and prefrontal cortex.