Tet Controls Axon Guidance in Early Brain Development through Glutamatergic Signaling.

Ten-eleven translocation (Tet) is an important gene in neurodevelopment, but how Tet regulates brain development is still under study. Mutations in human TET proteins have been found in individuals with neurodevelopmental disorders. Here we report a new function of Tet in regulating early brain development. We found that mutation on the Tet DNA-binding domain ( ) resulted in axon guidance defects in the mushroom body (MB). Tet is required in early brain development during the outgrowth of MB β axons. Transcriptomic study of mutant and wild-type pupal brains shows that glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is the most significantly down-regulated gene in the mutant brains. RNAi knockdown or CRISPR/Cas9 mutagenesis of Gs2 recapitulates the phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in the IPCs rescue the axonal defects of . Treating with the metabotropic glutamate receptor antagonist MPEP can also rescue the phenotype confirming Tet function in regulating glutamatergic signaling. and the homolog of mutant ( ) have similar mushroom body axonal defects and reduction in Gs2 transcription, and, importantly, overexpression of Gs2 in the IPCs of Fmr1 mutants also rescues the axonal defects. Our studies reveal a new function of Tet in regulating axon guidance in the brain via glutamatergic signaling and suggest overlapping functions between Tet and Fmr1.