Abstract
Mutations in human TET proteins have been found in individuals with neurodevelopmental disorders. Here we report a new function of Tet in regulating Drosophila early brain development. We found that mutation in the Tet DNA-binding domain ( Tet AXXC ) 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 shows that glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is significantly downregulated in the Tet AXXC mutant brains. CRISPR/Cas9 mutagenesis or RNAi knockdown of Gs2 recapitulates the Tet AXXC mutant phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in these cells rescues the axon guidance defects of Tet AXXC . Treating Tet AXXC with the metabotropic glutamate receptor antagonist MPEP can rescue while treating with glutamate enhances the phenotype confirming Tet function in regulating glutamatergic signaling. Tet AXXC and the Drosophila homolog of Fragile X Messenger Ribonucleoprotein protein mutant ( Fmr1 3 ) have similar axon guidance defects and reduction in Gs2 mRNA levels. Interestingly, overexpression of Gs2 in the IPCs also rescues the Fmr1 3 phenotype, suggesting functional overlapping of the two genes. Our studies provide the first evidence that Tet can control the guidance of axons in the developing brain by modulating glutamatergic signaling and the function is mediated by its DNA-binding domain.
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