Site-directed MT1-MMP trafficking and surface insertion regulate AChR clustering and remodeling at developing NMJs

Abstract

At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.

Dynamin-2 Regulates Postsynaptic Cytoskeleton Organization and Neuromuscular Junction Development

“…After development, NMJs are maintained to enable lifelong motor performance with restricted plasticity (Burden et al, 2018;Kummer et al, 2006;Shi et al, 2012). Although the intrinsic mechanism in muscle cells contributing to NMJ development remains poorly understood, a unique organelle, podosome, is found to locate at NMJs and promote their maturation (Chan et al, 2020;Proszynski et al, 2009).…”

“…Podosomes are protrusive actin structures equipped with ECM degrading abilities and are involved in immune cell patrolling, bone adsorption, and cancer cell metastasis (Linder, 2007;Linder and Aepfelbacher, 2003;Linder and Wiesner, 2016;Lux-enburg et al, 2007). Unlike the podosomes in motile cells that facilitate cell motility, podosomes at AChR clusters (synaptic podosomes) promote NMJ development by redistributing AChR and ECM components in cultured myotubes and mice (Bernadzki et al, 2014;Chan et al, 2020;Kishi et al, 2005;Proszynski and Sanes, 2013). Although the function of synaptic podosomes is critical for NMJ development, the dynamics and architecture of these structures are ill defined.…”

Grp94 Regulates the Recruitment of Aneural AChR Clusters for the Assembly of Postsynaptic Specializations by Modulating ADF/Cofilin Activity and Turnover

“…A previous study performed by single AChR tracking approach showed the contribution of surface AChR molecules, derived from either aneural clusters or diffuse receptor pool, to the sites of nerve-muscle contacts (Geng et al, 2009). Interestingly, a recent study further provided a definite evidence to demonstrate the recruitment of aneural AChR clusters for the assembly of nerve-induced synaptic AChR clusters (Chan et al, 2020b). Consistent with that, our present study confirmed the differential contribution of preexisting AChRs (from aneural clusters and diffuse AChRs) versus newly synthesized and inserted AChRs for the assembly of agrin-induced postsynaptic specializations (Fig.…”

Motor function recovery: deciphering a regenerative niche at the neuromuscular synapse

“…MACF1 interacts with the AChR‐binding protein rapsyn and serves as a postsynaptic organizer of microtubule and actin‐associated proteins in vivo (Oury et al ., 2019). Moreover, the induction of podosome‐like structures by extracellular matrix proteins has also been related to the assembly and topological remodelling of AChR clusters (Chan et al ., 2020). Mechanistically, this event is mediated by the trafficking and insertion of membrane‐type 1 matrix metalloproteinase (MT1‐MMP) to the cell surface which, in turn, is mediated by cytoskeleton‐dependent mechanisms (Chan et al ., 2020).…”