Tet controls axon guidance in early brain development through glutamatergic signaling

Mutations in ten-eleven translocation (TET) proteins are associated with human neurodevelopmental disorders. We find a function of Tet in regulating Drosophila early brain development. The Tet DNA-binding domain (Tet^AXXC) is required for axon guidance in the mushroom body (MB). Glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is significantly down-regulated in the Tet^AXXC brains. Loss of Gs2 recapitulates the Tet^AXXC phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in IPCs rescues the defects of Tet^AXXC. Feeding Tet^AXXC with metabotropic glutamate receptor antagonist MPEP rescues the phenotype while glutamate enhances it. Mutants in Tet and Drosophila Fmr1, the homolog of human FMR1, have similar defects, and overexpression of Gs2 in IPCs also rescues the Fmr1 phenotype. We provide the first evidence that Tet controls the guidance of developing brain axons by modulating glutamatergic signaling.