Atypical developmental remodeling of dopamine neurons involves AKT-GSK3β signaling and glia-mediated axon degeneration

Neuronal remodeling is essential for sculpting neural circuits, and its disruption has been implicated in neurodevelopmental and neuropsychiatric disorders. Yet the molecular and cellular diversity of remodeling across neuron types remains incompletely understood. Here, we uncover a distinct remodeling mode in a subtype of Drosophila dopamine neurons (DANs) critical for learning, memory, sleep, and locomotion. Unlike the stereotypical pruning-then-regrowth paradigm, these DANs undergo a transient axon overgrowth followed by selective pruning during metamorphosis. Remarkably, DAN axon pruning proceeds independently of canonical ecdysone signaling and instead involves neuron-intrinsic AKT-GSK3β signaling and extrinsic glial activity. Disruption of AKT-GSK3β signaling alters microtubule stability and impairs glial recruitment and clearance of axonal debris. Notably, the role of AKT-GSK3β is cell-type specific, underscoring mechanistic diversity in remodeling programs. These findings reveal an unexpected overgrowth-then-pruning developmental trajectory, establishing DANs as a powerful model to uncover the mechanisms underlying neuronal remodeling, circuit maturation, and neurodegeneration.