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Abstract
Neuronal migration and axonal outgrowth require precise guidance mechanisms during nervous system development. Amyloid precursor protein (APP) has been implicated in these processes, but its role in vivo remains unclear. Using the enteric nervous system of Manduca sexta, we show that its APP ortholog (APPL) interacts directly with the G protein Goα to regulate neuronal motility. Blocking APPL or Goα caused identical ectopic growth patterns, and similar APP-Goα interactions were confirmed in murine and human brain tissue. APP activation induced Go-dependent growth cone collapse, and phosphorylation at Thr668 modulated this interaction. These findings support APP family proteins as unconventional Goα-coupled receptors essential for neuronal guidance.