Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration

TTC5 mutations associate with cerebral atrophy, speech and motor impairment; however, the role of TTC5 and tubulin autoregulation in neuronal development are unknown. Using a human iPSC-derived cortical-like neuron model, we show that tubulin autoregulation is activated during neuronal differentiation and is TTC5-dependent.

Across differentiation, TTC5 loss suppresses microtubule polymerization and impairs axonal outgrowth and arborization. Moreover, TTC5 loss, or CRISPR knock-in of either an autoregulation-defective point mutant or previously uncharacterized patient disease mutants, unexpectedly stimulate neuronal motility. These phenotypes recapitulate in vivo where TTC5 loss in mouse cerebral cortex projection neurons (CPNs) alters axon arborization and promotes aberrant hypermigration.