Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration

Microtubule dynamics are essential for neuronal development, yet how neurons regulate tubulin levels remains poorly understood. Tetratricopeptide repeat domain 5 (TTC5) mediates tubulin autoregulation, the co-translational degradation of tubulin transcripts in response to excess soluble tubulin, and TTC5 mutations cause cerebral atrophy with speech and motor impairment. Here, we show that tubulin autoregulation is active in induced pluripotent stem cell (iPSC)-derived cortical neurons and depends on TTC5. TTC5 loss, or structure-guided mutations that disable autoregulation suppress microtubule polymerization, axonal outgrowth, and arborization, while enhancing cellular motility. Motility changes extend to non-neuronal cells, where they alter focal adhesion dynamics and can be rescued by manipulating soluble tubulin levels. Furthermore, downregulation of TTC5 interactor and autoregulation mediator S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) also suppresses neurite outgrowth and enhances motility. In vivo, TTC5 loss in mouse cortical projection neurons disrupts axon and dendrite arborization and causes hypermigration, recapitulating the cellular phenotypes observed in vitro. Patient-derived TTC5 disease mutants phenocopy this motility dysregulation, directly linking loss of TTC5 function to neurological deficits seen in patients. Together, these findings establish TTC5 as an essential regulator of neuronal morphogenesis and connectivity, with direct implications for TTC5-associated neurodevelopmental disease.