Nerve, Muscle, and Synaptogenesis

Abstract

The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several decades, a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.

Key concepts in muscle regeneration: muscle “cellular ecology” integrates a gestalt of cellular cross-talk, motility, and activity to remodel structure and restore function

“…The fascinating intricacies of nerve–muscle interaction, reviewed elsewhere (Delbono 2011 ; Shi et al 2012 ; Blaauw et al 2013 ; Witzemann et al 2013 ; English et al 2014 ; Tintignac et al 2015 ; Gordon and English 2016 ; Gordon and Borschel 2017 ; Cornish et al 2018 ; Macefield and Knellwolf 2018 ; Lepore et al 2019 ; Rudolf et al 2019 ; Swenarchuk 2019 ; Gordon 2020 ), underlie the essence of voluntary muscle function after regeneration, and depend on the extent and location of initial and secondary damage to fibers. Terminal Schwann cells (TSCs) bridge the synaptic cleft between axon terminals and the specialized sarcolemma at the NMJ (Barik et al 2016 ), help maintain synaptic structure (Reddy et al 2003 ; Feng et al 2005 ; Feng and Ko 2008 ), and also contribute to the satellite cell niche.…”

Skeletal Muscle Transcriptome Alterations Related to Physical Function Decline in Older Mice

“…Musk and Agrin genes are both downregulated significantly in older mice ( log2fc -0.627 and -0.390, respectively). Agrin acts to stabilize the MuSK receptor to the extracellular matrix and the cytoskeleton forming a focal point for ACHR clustering (Swenarchuk, 2019). Additionally, DOK4 is a peptide involved in neuronal outgrowth (gene log2fc -0.64) upstream of Rap1 (a g-coupled protein) and the ERK pathway.…”

The HSPG syndecan is a core organizer of cholinergic synapses

“…HSPGs bind multiple partners and can promote or regulate synaptogenesis ( Song and Kim 2013 ). The founding member of this diverse group is agrin, a large HSPG secreted by motoneurons at the vertebrate neuromuscular junctions (NMJs), which is absolutely required for NMJ differentiation and postsynaptic clustering of acetylcholine receptors (AChRs; Burden et al, 2018 ; Li et al, 2018 ; Swenarchuk, 2019 ). Since then, an increasing number of HSPGs, such as the glypicans 4 and 6, have been demonstrated to function as synaptic regulators ( Allen et al, 2012 ; Condomitti et al, 2018 ; reviewed in Condomitti and de Wit, 2018 ).…”