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• W2019900714 abstract "Motor neurons regulate neuromuscular junction formation by using agrin to stimulate acetylcholine receptor clustering and using acetylcholine to disperse unnecessary receptor clusters on muscle fibers. Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar now report in this issue of Developmental Cell a critical role for caspase-3 in intracellular mechanisms of acetylcholine-induced dispersal. Motor neurons regulate neuromuscular junction formation by using agrin to stimulate acetylcholine receptor clustering and using acetylcholine to disperse unnecessary receptor clusters on muscle fibers. Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar now report in this issue of Developmental Cell a critical role for caspase-3 in intracellular mechanisms of acetylcholine-induced dispersal. A synapse is a communicating contact between two neurons or a neuron and its target cell. It is fundamental to how we sense, think, and respond to the environment. Vast numbers of synapses are formed during embryonic development, presumably as a protective mechanism to ensure that all neurons are connected. Consequently, neonatal animals contain redundant, functionally immature synapses. To establish precise connectivity in the nervous system, during the postnatal period, excessive or inappropriate synapses are eliminated. This coincides with maturation of maintained synapses and occasional formation of new synapses. Moreover, the addition and disassembly of synapses are involved in activity-dependent plasticity in adult animals. Unlike synaptogenesis, which has been studied extensively, molecular mechanisms of synapse elimination are largely unknown. In this issue of Developmental Cell, Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar unravel an intracellular mechanism of synapse elimination. Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar studied the development of the neuromuscular junction (NMJ), a peripheral synapse between motor neurons and skeletal muscle fibers that uses acetylcholine (ACh) as a neurotransmitter. The NMJ has structural and functional features characteristic of a chemical synapse. Being large and easily accessible experimentally (compared with CNS synapses), the NMJ has contributed greatly to the understanding of general principles of synaptogenesis. Unlike a neuron in the brain that receives inputs from many synapses for information integration, a muscle fiber has no need to integrate signals but faithfully executes orders from a single motor neuron to ensure efficient and precise muscle contraction. Hence, in adult mammals, one muscle fiber has only one NMJ. In mice, prior to the arrival of motor axons, diaphragm muscle fibers form small, primitive AChR clusters (Figure 1A). These aneural clusters are dotted in the middle region of muscle fibers and outline a poorly defined central band—a phenomenon called prepatterning. Innervation by motor axons has to carry out two tasks: first, dispersal of the aneural AChR clusters, and second, induction of large AChR clusters, some of which may be converted from aneural ones, to form premature NMJs. At birth, the premature NMJs appear like plaques and often are convergently innervated by multiple neurons. In the ensuing two weeks, the number of motor axons innervating each muscle fiber is reduced to one and the NMJs appear as characteristic “pretzels” in shape (Figure 1A) (Wu et al., 2010Wu H. Xiong W.C. Mei L. Development. 2010; 137: 1017-1033Crossref PubMed Scopus (412) Google Scholar). Motor neurons induce AChR clusters by releasing agrin, which binds to LRP4, a member of the low-density lipoprotein receptor family, and activates the receptor tyrosine kinase MuSK (Wu et al., 2010Wu H. Xiong W.C. Mei L. Development. 2010; 137: 1017-1033Crossref PubMed Scopus (412) Google Scholar). Downstream of the agrin/LRP4/MuSK pathway, Dok7 is believed to promote MuSK activity and rapsyn is believed to bridge the AChR with the cytoskeleton (Wu et al., 2010Wu H. Xiong W.C. Mei L. Development. 2010; 137: 1017-1033Crossref PubMed Scopus (412) Google Scholar). Much less is known about how extra AChR clusters or synapses are eliminated during development. In mutant mice lacking choline acetyltransferase (ChAT), the ACh biosynthetic enzyme, AChR clusters are increased in number and populate a broader area of muscle (Brandon et al., 2003Brandon E.P. Lin W. D’Amour K.A. Pizzo D.P. Dominguez B. Sugiura Y. Thode S. Ko C.P. Thal L.J. Gage F.H. Lee K.F. J. Neurosci. 2003; 23: 539-549PubMed Google Scholar, Misgeld et al., 2002Misgeld T. Burgess R.W. Lewis R.M. Cunningham J.M. Lichtman J.W. Sanes J.R. Neuron. 2002; 36: 635-648Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar), suggesting that motor neurons use ACh to disperse aneural AChR clusters and restrict induced clusters within the central region. The effect of ACh is thought to be mediated by cyclin-dependent kinase 5 (Cdk5) (Fu et al., 2005Fu A.K. Ip F.C. Fu W.Y. Cheung J. Wang J.H. Yung W.H. Ip N.Y. Proc. Natl. Acad. Sci. USA. 2005; 102: 15224-15229Crossref PubMed Scopus (88) Google Scholar, Lin et al., 2005Lin W. Dominguez B. Yang J. Aryal P. Brandon E.P. Gage F.H. Lee K.F. Neuron. 2005; 46: 569-579Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). There are two models explaining how muscle activity stimulates Cdk5 (Figure 1B). In one, a more potent activator, p25, is produced by the protease calpain, which is inhibited by rapsyn (Chen et al., 2007Chen F. Qian L. Yang Z.H. Huang Y. Ngo S.T. Ruan N.J. Wang J. Schneider C. Noakes P.G. Ding Y.Q. et al.Neuron. 2007; 55: 247-260Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). In another, p35 is recruited to Cdk5, which is associated with the intermediate filament protein nestin (Yang et al., 2011Yang J. Dominguez B. de Winter F. Gould T.W. Eriksson J.E. Lee K.F. Nat. Neurosci. 2011; 14: 324-330Crossref PubMed Scopus (37) Google Scholar). Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar identify a pathway that is critical in eliminating aneural AChR clusters. They investigated mechanisms of CCh, a nonhydrolyzable AChR agonist that disperses AChR clusters in muscle cells (Chen et al., 2007Chen F. Qian L. Yang Z.H. Huang Y. Ngo S.T. Ruan N.J. Wang J. Schneider C. Noakes P.G. Ding Y.Q. et al.Neuron. 2007; 55: 247-260Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, Lin et al., 2005Lin W. Dominguez B. Yang J. Aryal P. Brandon E.P. Gage F.H. Lee K.F. Neuron. 2005; 46: 569-579Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar), and find that it stimulates caspase-3, a protease implicated in apoptosis. To determine whether caspase-3 can be activated in a physiological setting, the authors expressed channelrhodopsin-2 in motor neurons and cocultured them with myotubes. Laser stimulation of transfected motor neurons led to activation of caspase-3 in areas of noninnervated AChR clusters. These experiments elegantly demonstrated that presynaptic activity of motor neurons could activate caspase-3 in muscle. Remarkably, CCh-stimulated elimination of AChR clusters was attenuated by pharmacological inhibition or genetic ablation of caspase-3 in cultured muscles. In agreement, caspase-3 mutation increased the number of aneural AChR clusters in embryonic diaphragm. These observation corroborate that caspase-3 is a mediator of muscle activity to eliminate aneural AChR clusters. How does caspase-3 work? Local activation of caspase-3 by CCh did not cause cell death but instead regulated AChR clusters in an unexpected manner. Dishevelled (Dvl1) is an adaptor protein implicated in Wnt signaling; Dvl1 has been previously shown to bridge a MuSK-Dvl1-PAK1 complex for agrin-induced AChR clustering (Luo et al., 2002Luo Z.G. Wang Q. Zhou J.Z. Wang J. Luo Z. Liu M. He X. Wynshaw-Boris A. Xiong W.C. Lu B. Mei L. Neuron. 2002; 35: 489-505Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). In an elegant set of biochemical and cell biology experiments, Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar demonstrate that CCh stimulation causes cleavage of Dvl1, and that inhibition of Dvl1 cleavage prevents cluster dispersal by CCh or by motor neuron activation. Expression of a caspase-3-resistant form of Dvl1 by chest viral infection increased the number of aneural AChR clusters in the embryonic diaphragm. CCh also reduced the interaction between MuSK and Dvl1 and dispersed agrin-induced clusters of APC, a microtubule-regulator protein implicated in both Wnt signaling and AChR clustering (Wu et al., 2010Wu H. Xiong W.C. Mei L. Development. 2010; 137: 1017-1033Crossref PubMed Scopus (412) Google Scholar). APC appears to act downstream of Dvl1, because CCh-induced dispersal of APC clusters was inhibited by preventing Dvl1 cleavage. Finally, CCh-induced caspase-3 activity or cluster dispersal was inhibited by 17-AAG, an inhibitor of HSP90β, suggesting that HSP90β helps keep caspase-3 in check, in addition to protecting rapsyn (Luo et al., 2008Luo S. Zhang B. Dong X.P. Tao Y. Ting A. Zhou Z. Meixiong J. Luo J. Chiu F.C. Xiong W.C. Mei L. Neuron. 2008; 60: 97-110Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). The findings of Wang et al., 2014Wang J.Y. Chen F. Fu X.Q. Ding C.S. Zhou L. Zhang X.H. Luo Z.G. Dev. Cell. 2014; 28 (this issue): 670-684Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar are provocative and reveal a role for caspase-3 in synaptogenesis. They also raise many questions. Is this mechanism involved in postnatal synapse elimination or conversion of multi-innervated NMJs to mature ones with a single motor neuron terminal (Figure 1A)? Is it involved in sculpting the postsynaptic membrane for “pretzel-like” morphology? These questions could be addressed by studies of caspase-3 mutant mice, because they survive to 6 months of age. The rescue effect of caspase-3 ablation in agrin mutant mice appears to be partial, suggesting the existence of other effectors. What is the relationship of caspase-3 with these effectors, for example Cdk5 and its regulators? Dvl1 and APC are mediators of Wnt signaling. Considering recent studies implicating Wnts in NMJ formation (Wu et al., 2010Wu H. Xiong W.C. Mei L. Development. 2010; 137: 1017-1033Crossref PubMed Scopus (412) Google Scholar), it would be interesting to determine whether caspase-3-mediated Dvl1 cleavage acts by altering Wnt pathways. The results of this paper also call for future studies to determine whether caspase-3 is involved in CNS synapse pruning. Caspase-3 Cleavage of Dishevelled Induces Elimination of Postsynaptic StructuresWang et al.Developmental CellMarch 13, 2014In BriefSynaptic pruning is an essential process during the formation of precise neuronal connections. Wang et al. uncover a nonapoptotic role of caspase-3 in the refinement of neuromuscular synapses via dispersion of acetylcholine receptor (AChR) clustering. Cholinergic stimulation activates caspase-3, which acts on Dishevelled, a Wnt signaling protein involved in AChR clustering. Full-Text PDF Open Archive" @default.
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