Lose it to use it

In this issue, Wang et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.201911114) describe a phenomenon in which neuromuscular junction synapse elimination triggers myelination of terminal motor axon branches. They propose a mechanism initiated by synaptic pruning that depends on synaptic activity, cytoskeletal maturation, and the associated anterograde transport of trophic factors including Neuregulin 1-III.

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.

Regeneration of spinal motor axons: Negative regulation by Celsr2 implicating Cdc42/Rac1 and JNK/c-Jun signaling

During development, cadherins Celsr2 and Celsr3 control axon navigation. Unlike Celsr3, Celsr2 remains expressed in the adult, suggesting unexplored roles in maintenance and repair. Here we show that Celsr2 knockdown promotes motor axon regeneration in mouse and human spinal cord explants and cultured motor neurons. Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun proteins. Using a branchial plexus injury model, we show that forelimb functional recovery is improved in Celsr2 mutant versus control mice. Compared to controls, in mutant mice, reinnervated biceps muscles are less atrophic, contain more newly formed neuromuscular junctions, and generate larger electromyographic potentials, while motor neuron survival and axon regeneration are improved. GTP-bound Rac1 and Cdc42, JNK and c-Jun are upregulated in injured mutant versus control spinal cord. In conclusion, Celsr2 negatively regulates motor axon regeneration via Cdc42/Rac1/JNK/c-Jun signaling and is a target for neural repair.

Decreased excitability of motor axons contributes substantially to contraction fatigability during neuromuscular electrical stimulation

The present study was designed to: 1) determine the time course of changes in motor axon excitability during and after neuromuscular electrical stimulation (NMES), and 2) characterise the relationship between contraction fatigability, NMES frequency, and changes at the axon, neuromuscular junction, and muscle. Eight neurologically-intact participants attended three sessions. NMES was delivered over the common peroneal nerve at 20, 40, or 60 Hz for 8 min (0.3 s “on”, 0.7 s “off”). Threshold tracking was used to measure changes in axonal excitability. Supramaximal stimuli were used to assess neuromuscular transmission and force-generating capacity of the tibialis anterior muscle. Torque decreased 49 and 62% during 8 min of 40 and 60 Hz NMES, respectively. Maximal twitch torque decreased only during 60 Hz NMES. Motor axon excitability decreased by 14, 27, and 35% during 20, 40, and 60 Hz NMES, respectively. Excitability recovered to baseline immediately (20 Hz), 2 min (40 Hz), and 4 min (60 Hz) following NMES. Overall, decreases in axonal excitability best predicted how torque declined over 8 min of NMES. During NMES, motor axons become less excitable and motor units “drop out” of the contraction, contributing substantially to contraction fatigability and its dependence on NMES frequency. NOVELTY BULLETS • The excitability of motor axons decreased during neuromuscular electrical stimulation (NMES) in a frequency-dependent manner. • As excitability decreased, axons failed to reach threshold and motor units dropped out of the contraction. • Overall, decreased excitability best predicted how torque declined and thus is a key contributor to fatigability during NMES.