The neuron-intrinsic membrane skeleton is required for motor neuron integrity throughout lifespan.

Axons experience physical stress throughout an organism's lifetime, and disruptions in axonal integrity are hallmarks of both neurodegenerative diseases and traumatic injuries. The spectrin-based membrane periodic skeleton (MPS) is proposed to have a crucial role in maintaining axonal strength, flexibility, and resilience. To investigate the importance of the intrinsic MPS for GABAergic motor neuron integrity in C. elegans, we employed the auxin-inducible degron system to degrade β-spectrin/UNC-70 in a cell-type specific and time-dependent manner. Degradation of β-spectrin from all neurons beginning at larval development resulted in widespread axon breakage and regeneration in VD/DD GABAergic motor neurons in both larval and adult animals. Similarly, targeted degradation of β-spectrin in GABA neurons alone resulted in extensive breakage. Moreover, we found that depleting β-spectrin from the mature nervous system also induced axon breaks. By contrast, epidermal β-spectrin was not required for axon integrity of VD/DD neurons. These findings demonstrate the cell-intrinsic importance of neuronal β-spectrin/UNC-70 for axon integrity both during development and in adulthood.