METTL9 sustains vertebrate neural development primarily via non-catalytic functions

METTL9 is an enzyme catalysing histidine N1-methylation (1-MH). Given the high levels of this methyltransferase during vertebrate nervous system development, we dissected the roles of Mettl9 during this relevant physiological process. We generated three mouse embryonic stem cell lines featuring a complete Mettl9 knock-out, an inducible degron system, and the endogenous expression of a catalytically inactive protein. Additionally, we employed Xenopus laevis to down-regulate Mettl9 during neural development in vivo. Our multi-omic data indicate that METTL9 exerts a conserved role in sustaining vertebrate neurogenesis. Surprisingly, both perturbation of METTL9 catalytic activity and depletion of METTL9 protein levels without affecting global 1-MH levels show milder neural commitment defects, suggesting a role for both METTL9 catalytic and non-enzymatic activities. These converge towards the secretory pathway, where METTL9 co-localises with the Golgi apparatus and interacts with key regulators of cellular transport, endocytosis and Golgi integrity.