A research group led by Professor Noriko Osumi of Tohoku University Graduate School, in collaboration with Tokyo University of Agriculture and Aichi Devlopmental Health and Rehabilitation Center, can cause aging of fathers to cause neurodevelopmental disorders-like behavioral abnormalities in pups, and the causes. For the first time, we have clarified a part of the molecular basis.

 Neurodevelopmental disorders in children such as mental retardation and autism spectrum disorders are increasing, which is a big problem in an aging society with a declining birthrate.In recent years, it has been known that the risk of developmental disorders in children is more related to the age of the father than to the mother, but the mechanism is unknown.

 Mice 1 to 2 weeks old use ultrasonic vocalization to communicate voice between mother and baby.In this study, we found that pups born to father mice 12 months of age or older (aged) show neurodevelopmental disorder-like behavioral abnormalities such as decreased frequency of ultrasonic vocalization and monotonic crying.In addition, 96 DNA hypomethylated regions were confirmed in the sperm DNA of aged mice.The binding sequence of the protein (REST / NRSF) that controls neural differentiation was frequently present in the sequence of this region.

 Therefore, when we examined the embryonic brain in which neurogenesis was active, the activity of autism-related genes was strong in the fetal brain derived from the aging father mouse, and the target gene of REST / NRSF was highly expressed.Furthermore, when DNA hypomethylation was induced in young father mice, the frequency of ultrasonic vocalizations decreased in the born pups, and the pattern of how they squeal became monotonous.

 This suggests that aging-related neurodevelopmental disorders in children involve hypomethylation of sperm DNA, and that its molecular mechanism may be due to REST / NRSF-mediated neurogenesis abnormalities.In the future, it is expected that prevention and treatment of neurodevelopmental disorders will be promoted by preventing the hypomethylation of DNA and its influence on the next generation due to aging.

Paper information:[EMBO Reports] Paternal age affects offspring via an epigenetic mechanism involving REST / NRSF

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