Dynamin-2 Regulates Postsynaptic Cytoskeleton Organization and Neuromuscular Junction Development

Shan-Shan Lin,Tsung-Lin Hsieh,Gunn-Guang Liou,Tsai-Ning Li,Hsin-Chieh Lin,Chiung-Wen Chang,Hsiang-Yi Wu,Chi-Kuang Yao,Ya-Wen Liu

doi:10.1016/j.celrep.2020.108310

Shan-Shan Lin, Tsung-Lin Hsieh + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2020.108310

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Abstract

Neuromuscular junctions (NMJs) govern efficient neuronal communication with muscle cells, relying on proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to NMJ development remains unclear. In this study, we reveal that dynamin-2 (Dyn2) is involved in postsynaptic development of NMJs. Mutations of Dyn2 have been linked to human muscular disorder and centronuclear myopathy (CNM), as well as featured with muscle atrophy and defective NMJs, yet the function of Dyn2 at the postsynaptic membrane is largely unknown. We demonstrate that Dyn2 is enriched at the postsynaptic membrane and regulates NMJ development via actin remodeling. Dyn2 functions as an actin-bundling GTPase to regulate podosome turnover and cytoskeletal organization of the postsynaptic apparatus, and CNM-Dyn2 mutations display abnormal actin remodeling and electrophysiological activity of fly NMJs. Altogether, Dyn2 primarily regulates actin cytoskeleton remodeling and NMJ morphogenesis at the postsynaptic membrane, which is distinct from its endocytosis regulatory role at the presynaptic membrane.

Highlights

Neuromuscular junctions (NMJs) control the final output of the nervous system to direct voluntary movements and are equipped with elaborate membranous and cytoskeletal structures developed from a stepwise process of morphogenesis (Sanes and Lichtman, 2001)
Dyn2 has been reported to be enriched in synaptic podosome and is required for the perforation of acetylcholine receptors (AChRs) clusters (Proszynski et al, 2009). These findings indicate an important role of Dyn2 in postsynaptic NMJs; the molecular function of Dyn2 at the postsynaptic membrane has not been extensively investigated
We reveal that Dyn2 functions as an actin-remodeling guanosine triphosphatase (GTPase) at the postsynaptic membrane, where Dyn2 promotes AChR cluster perforation and further organizes the postsynaptic cytoskeleton to maintain the function of NMJs

Summary

Introduction

Neuromuscular junctions (NMJs) control the final output of the nervous system to direct voluntary movements and are equipped with elaborate membranous and cytoskeletal structures developed from a stepwise process of morphogenesis (Sanes and Lichtman, 2001). The plaque-to-pretzel transition requires extracellular matrix (ECM) signaling, motor neuron activity, and muscle-intrinsic machineries (Bernadzki et al, 2014; Bezakova and Ruegg, 2003; Marques et al, 2000; Shi et al, 2012). 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). The function of synaptic podosomes is critical for NMJ development, the dynamics and architecture of these structures are ill defined

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