m⁶A modulates neuronal functions and sex determination in Drosophila

N⁶-methyladenosine RNA (m⁶A) is a prevalent messenger RNA modification in vertebrates. Although its functions in the regulation of post-transcriptional gene expression are beginning to be unveiled, the precise roles of m⁶A during development of complex organisms remain unclear. Here we carry out a comprehensive molecular and physiological characterization of the individual components of the methyltransferase complex, as well as of the YTH domain-containing nuclear reader protein in Drosophila melanogaster. We identify the member of the split ends protein family, Spenito, as a novel bona fide subunit of the methyltransferase complex. We further demonstrate important roles of this complex in neuronal functions and sex determination, and implicate the nuclear YT521-B protein as a main m⁶A effector in these processes. Altogether, our work substantially extends our knowledge of m⁶A biology, demonstrating the crucial functions of this modification in fundamental processes within the context of the whole animal.