IGF2BP2-Shox2 axis regulates hippocampal- neuronal senescence to alleviate microgravity-induced recognition disturbance

During space travel, microgravity leads to disturbance in cognitive function, while the underlying mechanism is still unclear. Simulated microgravity mice showed neuronal age-like changes in the hippocampus and increased expression of age-related genes. In the context of microgravity, we discovered m6A modification reshapes in the hippocampal region. When paired with RNA-seq and MeRIP-seq, Shox2 was found to be a powerful regulator in hippocampal neuron that responded to microgravity. Decreased expression of senescence-associated secretory phenotype factors and improved genes related to synapses led to the restoration of memory function in the hippocampus upon increased expression of Shox2. Moreover, we discovered that IGF2BP2 was required for the m6A modification of the Shox2, and overexpressed IGF2BP2 in the hippocampus protected against both neuronal senescence and learning and memory decline brought by loss of gravity. Accordingly, our research identified the hippocampal IGF2BP2-Shox2 axis as a possible therapeutic approach to maintain cognitive function during space travel, and perhaps even during further deep space exploration in the future.