Neuronal development requires UFMylation

Neurodevelopmental disorders (NDDs) have a highly heterogeneous etiology but share dysfunctional molecular pathways whose characterization is necessary for therapy development. Recently, NDDs have been linked to defects in UFMylation, a post-translational protein modification that involves the covalent and reversible attachment of UFM1 to targets via the orchestrated action of specific enzymes. Interestingly, mutations in the human Ufm1 gene or in genes encoding UFM1-conjugating enzymes have been associated with NDDs. These mutations all cause reduced UFMylation in the brain, providing striking evidence that UFM1-conjugation plays a critical role in brain development and function. However, the functional role of UFMylation in the brain remains largely unknown. To advance our understanding of brain UFMylation and its role in NDDs, we examined the brains and neurons of UFM1 knock-out mice. We found that depletion of UFM1 causes cortical neurodevelopmental abnormalities. Using immunolabeling and electrophysiological recordings in autaptic hippocampal neuron cultures, we discovered that UFM1-loss results in reduced neurite complexity, reduced synapse numbers, and corresponding changes in synaptic transmission. At the molecular level, these phenotypic changes are paralleled by reduced neuronal protein translation. Our data show that UFMylation co-controls neuronal development and differentiation, at least in part by guaranteeing proper protein synthesis.