Completion of neuronal remodeling prompts myelination along developing motor axon branches

Abstract

Neuronal remodeling and myelination are two fundamental processes during neurodevelopment. How they influence each other remains largely unknown, even though their coordinated execution is critical for circuit function and often disrupted in neuropsychiatric disorders. It is unclear whether myelination stabilizes axon branches during remodeling or whether ongoing remodeling delays myelination. By modulating synaptic transmission, cytoskeletal dynamics, and axonal transport in mouse motor axons, we show that local axon remodeling delays myelination onset and node formation. Conversely, glial differentiation does not determine the outcome of axon remodeling. Delayed myelination is not due to a limited supply of structural components of the axon–glial unit but rather is triggered by increased transport of signaling factors that initiate myelination, such as neuregulin. Further, transport of promyelinating signals is regulated via local cytoskeletal maturation related to activity-dependent competition. Our study reveals an axon branch–specific fine-tuning mechanism that locally coordinates axon remodeling and myelination.

Lose it to use it

“…Taken together, the experiments performed by Wang et al (2) suggest that as multiple axons actively compete for synaptic dominance at the NMJ, the myelination of their terminal branches is delayed. Upon synapse elimination, neuromuscular activity promotes a retrograde signal that increases maturity of the microtubule cytoskeleton.…”

“…These two axons then further compete for synaptic territory, leaving one "winner" that eventually occupies the motor endplate by the end of the second postnatal week. To determine the relationship between synapse elimination and myelination, Wang et al (2) used the formation of paranodal junctions between axons and Schwann cells as a surrogate for myelination and then determined whether axons that occupied NMJs in a singly or dually innervated state were more or less likely to be myelinated. They found that when the NMJ is dually innervated, myelination of the terminal axon branch is inhibited; neither synaptic occupancy of the competing axons nor axon diameter influenced myelination.…”

“…What mechanisms regulate the coordinated maturation of the motor neuron, Schwann cell, and muscle circuit? Since previous studies showed that synapse elimination at the NMJ depends on muscle activity (3), Wang et al (2) inhibited synapse elimination by blocking acetylcholine receptors with α-bungarotoxin (α-Btx). This inhibition of motor endplate and muscle activity increased not only the number of dually innervated NMJs, but also significantly decreased myelination of terminal axon branches of singly innervated NMJs.…”

The Cortical Motor System in the Domestic Pig: Origin and Termination of the Corticospinal Tract and Cortico-Brainstem Projections

“…CST myelination likewise occurs in the postnatal period in domestic pigs, reaching a mature state by 6 postnatal months ( Fang et al, 2005 ). Because completion of neural circuit formation and myelination of axonal branches are interrelated events ( Wang et al, 2021 ), no major changes are expected in the healthy cortical motor system connectivity after the first half-year of postnatal life in domestic pigs, except for changes in the number of axonal endings, synaptic maturation, and physiological remodeling associated to learning and neural activity ( Martin, 2005 ). In this regard, development of corticomotoneuronal connections deserves consideration.…”

Dynamic early clusters of nodal proteins contribute to node of Ranvier assembly during myelination of peripheral neurons

“…Triangularis sterni explants were isolated as previously described ( Kerschensteiner et al, 2008 ; Wang et al, 2021 ) from mice expressing a SEP-Nfasc186 transgene on either a WT, Nfasc -/- , or Cntnap1 -/- background. Following dissection of the thorax, the nerve muscle explant was pinned using minutin pins (Fine Science Tools) in a 40 mm inner well of a 60 mm Sylgard 184-coated dish containing oxygenated (95% O 2 , 5% CO 2 ) and cooled Ringers solution (125 mM NaCl, 2.5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 1.25 NaH 2 PO 4 , 26 mM NaHCO 3 , 20 mM glucose).…”