Drosophila Graf regulates mushroom body β-axon extension and olfactory long-term memory

Loss-of-function mutations in the human oligophrenin-1 (OPHN1) gene cause intellectual disability, a prevailing neurodevelopmental condition. However, the role OPHN1 plays during neuronal development is not well understood. We investigated the role of the Drosophila OPHN1 ortholog Graf in the development of the mushroom body (MB), a key brain structure for learning and memory in insects. We show that loss of Graf causes abnormal crossing of the MB beta lobe over the brain midline during metamorphosis. This defect in Graf mutants is rescued by MB-specific expression of Graf and OPHN1. Furthermore, MB alpha/beta neuron-specific RNA interference experiments and mosaic analyses indicate that Graf acts via a cell-autonomous mechanism. Consistent with the negative regulation of epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) signaling by Graf, activation of this pathway is required for the beta-lobe midline-crossing phenotype of Graf mutants. Finally, Graf mutants have impaired olfactory long-term memory. Our findings reveal a role for Graf in MB axon development and suggest potential neurodevelopmental functions of human OPHN1.

Automated summary

Loss-of-function mutations in the human OPHN1 gene lead to intellectual disability, and the Drosophila ortholog of OPHN1, Graf, plays a critical role in the development of the mushroom body. The defects in Graf mutants can be rescued by MB-specific expression of Graf and OPHN1, indicating a potential neurodevelopmental role of human OPHN1.