Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration

Abstract

Microtubule dynamics regulation is critical for neuronal development, yet how neurons regulate tubulin levels remains poorly understood. Tetratricopeptide repeat domain 5 (TTC5) mediates the co-translational degradation of tubulin transcripts in response to excess soluble tubulin, a.k.a. "tubulin autoregulation", and TTC5 mutations are associated with cerebral atrophy, speech and motor impairment. Despite clinical relevance, the role of TTC5 and tubulin autoregulation in neurons has not been established. Using human induced pluripotent stem cells (iPSCs)-derived cortical-like neurons, we demonstrate that tubulin autoregulation is active in neurons and fully TTC5-dependent. Loss of TTC5 function suppresses microtubule polymerization and impairs axonal outgrowth and arborization, while enhancing cellular motility. These phenotypes recapitulate in vivo where TTC5 loss in mouse cerebral cortex projection neurons disrupts axon and dendrite arborization and drives aberrant hypermigration. Patient disease mutants phenocopy this motility dysregulation, directly linking TTC5 dysfunction to clinically relevant neurological deficits. Together, our findings establish tubulin autoregulation and its mediators as essential regulators of neuronal morphogenesis and connectivity and provides a mechanistic framework for understanding TTC5-associated neurodevelopmental disease.