Evolution of Osteocrin as an activity-regulated factor in the primate brain

Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates. Osteocrin is a non-neuronal secreted protein in mice that has been evolutionarily repurposed to act as a neuronal development factor in primates. Much of the research on the gene expression networks that drive brain development has been performed in mice. Relatively little is known about how expression networks in other animal groups—particularly primates, in which the cerebral cortex is expanded—might differ from the mouse model. Here, Michael Greenberg and colleagues identify a non-neuronal secreted factor in mice, Osteocrin, that may have been re-purposed evolutionarily as a neuronal development gene in primates. Osteocrin is specifically expressed in the neocortex of the humans and macaques. In mice it is enriched in bone and muscle tissues, but not in the brain.