Tubulin autoregulation factors recruit γ-tubulin to non-centrosomal MTOCs for neuronal microtubule nucleation

Abstract

Abstract Neuronal function and survival depend on highly stereotyped non-centrosomal microtubule (MT) arrays. How these arrays form remains poorly understood. Here we identified a role for SCAPER and TTC5, two factors previously implicated in tubulin mRNA autoregulation, in controlling neuronal MT content through γ-tubulin-dependent nucleation. In C. elegans neurons, loss of scpr-1, ttc-5, or both reduced MT numbers to a similar degree as depletion of γ-tubulin, the main MT nucleator. Using conditional single-cell degradation alleles and endogenous tagging, we find that γ-tubulin nucleates MTs in the neuronal cell body from endosomal puncta, and that scpr-1 and ttc-5 are required to recruit γ-tubulin to these structures. SCPR-1 is also instructive, as its overexpression drastically increases γ-tubulin levels and enhances MT density. We propose that these mechanisms are conserved since human SCAPER rescues C. elegans mutants, and SCAPER knockdown in rat hippocampal neurons reduces both γ-tubulin clustering at presynaptic sites and activity-dependent synaptic MT nucleation. Finally, while scpr-1, ttc-5, and γ-tubulin are not required for developmental axon elongation, they are essential for regeneration, where SCPR-1 directs γ-tubulin to the growth cone to facilitate regrowth following injury. These findings reveal mechanisms governing neuronal cytoskeleton assembly and function, and suggest potential crosstalk between tubulin autoregulation and microtubule nucleation.

The authors' abstract, as published at the source. Current Biology, 2026 · DOI ↗