期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：39
DOI：10.1073/pnas.2109040118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Adult neurogenesis, which is known to be a heritable trait, is thought to be involved in learning, stress-related anxiety, and antidepressant action. In this study, we map genes influencing adult neurogenesis and identify a candidate gene, follistatin (
Fst) for further study. By utilizing a brain-specific knockout and viral vector-mediated gene transfer, we reveal the importance of hippocampal FST in neurogenesis, learning, and synaptic plasticity. From RNA sequencing and chromatin immunoprecipitation experiments, we identify
Asic4 as a critical downstream target gene regulated by FST. Our work demonstrates that FST functions in the hippocampus at least in part through regulating
Asic4 expression. Overall, we illustrate the role of hippocampal
Fst in learning and synaptic plasticity.
The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin (
Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific
Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning.
Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of
Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified
Asic4 as a target gene regulated by FST and show that
Asic4 plays a critical role in learning deficits caused by
Fst deletion. Long-term overexpression of hippocampal
Fst in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.
