Postsynaptic CaV1.1-driven calcium signaling coordinates presynaptic differentiation at the developing neuromuscular junction.

Published on Dec 5, 2019in Scientific Reports4.011
· DOI :10.1038/S41598-019-54900-W
Mehmet Mahsum Kaplan2
Estimated H-index: 2
Bernhard E. Flucher37
Estimated H-index: 37
Proper formation of neuromuscular synapses requires the reciprocal communication between motor neurons and muscle cells. Several anterograde and retrograde signals involved in neuromuscular junction formation are known. However the postsynaptic mechanisms regulating presynaptic differentiation are still incompletely understood. Here we report that the skeletal muscle calcium channel (CaV1.1) is required for motor nerve differentiation and that the mechanism by which CaV1.1 controls presynaptic differentiation utilizes activity-dependent calcium signaling in muscle. In mice lacking CaV1.1 or CaV1.1-driven calcium signaling motor nerves are ectopically located and aberrantly defasciculated. Axons fail to recognize their postsynaptic target structures and synaptic vesicles and active zones fail to correctly accumulate at the nerve terminals opposite AChR clusters. These presynaptic defects are independent of aberrant AChR patterning and more sensitive to deficient calcium signals. Thus, our results identify CaV1.1-driven calcium signaling in muscle as a major regulator coordinating multiple aspects of presynaptic differentiation at the neuromuscular synapse.
  • References (50)
  • Citations (1)
📖 Papers frequently viewed together
20 Citations
1 Author (Mahru C. An)
713 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#2Nasreen SultanaH-Index: 2
Last. Bernhard E. FlucherH-Index: 37
view all 9 authors...
Summary Formation of synapses between motor neurons and muscles is initiated by clustering of acetylcholine receptors (AChRs) in the center of muscle fibers prior to nerve arrival. This AChR patterning is considered to be critically dependent on calcium influx through L-type channels (CaV1.1). Using a genetic approach in mice, we demonstrate here that either the L-type calcium currents (LTCCs) or sarcoplasmic reticulum (SR) calcium release is necessary and sufficient to regulate AChR clustering ...
2 CitationsSource
#1Lei Li (Case Western Reserve University)H-Index: 10
#2Wen Cheng XiongH-Index: 53
Last. Lin MeiH-Index: 60
view all 3 authors...
Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneuro...
31 CitationsSource
#1Anamika Dayal (Innsbruck Medical University)H-Index: 6
#2Kai Schrötter (Innsbruck Medical University)H-Index: 2
Last. Manfred Grabner (Innsbruck Medical University)H-Index: 34
view all 6 authors...
Skeletal muscle excitation–contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and l-type Ca2+ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conven...
12 CitationsSource
#1Bernhard E. FlucherH-Index: 37
#2Petronel Tuluc (University of Innsbruck)H-Index: 16
Voltage-gated calcium channels represent the sole mechanism converting electrical signals of excitable cells into cellular functions such as contraction, secretion, and gene regulation. Specific voltage-sensing domains detect changes in membrane potentials and control channel gating. Calcium ions entering through the channel function as second messengers regulating cell functions; with the exception of skeletal muscle, where CaV1.1 is essentially not functioning as channel but activates calcium ...
10 CitationsSource
#1Nasreen SultanaH-Index: 2
#2Beatrix Dienes (University of Debrecen)H-Index: 25
Last. Bernhard E. FlucherH-Index: 37
view all 12 authors...
Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Whether this is necessary for normal development and function of muscle is not known. However, splicing defects causing aberrant expression of the calcium-conducting developmental CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon ...
17 CitationsSource
#1Haitao Wu (Georgia Regents University)H-Index: 9
#2Arnab Barik (Georgia Regents University)H-Index: 14
Last. Lin Mei (Georgia Regents University)H-Index: 60
view all 10 authors...
Motor nerves are like electrical wires that connect our spinal cord to the muscles in our body. These nerves communicate with muscles across a connection called the neuromuscular junction. To first form a neuromuscular junction, the motor nerves and muscles each produce molecular cues that tell each other to do their part to build a connection. Beta-catenin in the muscle is known to regulate motor nerve development. However, beta-catenin has two different roles: it helps to coordinate whether ne...
30 CitationsSource
#1Bruno BenedettiH-Index: 10
#2Petronel Tuluc (University of Innsbruck)H-Index: 16
Last. Bernhard E. FlucherH-Index: 37
view all 5 authors...
CaV1.1e is the voltage-gated calcium channel splice variant of embryonic skeletal muscle. It differs from the adult CaV1.1a splice variant by the exclusion of exon 29 coding for 19 amino acids in the extracellular loop connecting transmembrane domains IVS3 and IVS4. Like the adult splice variant CaV1.1a, the embryonic CaV1.1e variant functions as voltage sensor in excitation-contraction coupling, but unlike CaV1.1a it also conducts sizable calcium currents. Consequently, physiological or pharmac...
10 CitationsSource
#1Toshikatsu HanadaH-Index: 33
#2Stefan WeitzerH-Index: 7
Last. Josef M. PenningerH-Index: 130
view all 24 authors...
Inactivating the CLP1 RNA kinase in mice leads to a progressive loss of motor neurons, through a mechanism related to the accumulation of a novel set of small RNA fragments derived from aberrant processing of tyrosine pre-transfer RNA.
101 CitationsSource
#1Norihiro Yumoto (NYU: New York University)H-Index: 3
#2Natalie Kim N (NYU: New York University)H-Index: 7
Last. Steven J. Burden (NYU: New York University)H-Index: 47
view all 3 authors...
Lrp4 acts bidirectionally and coordinates synapse formation by binding agrin, activating MuSK and stimulating postsynaptic differentiation, and functioning in turn as a muscle-derived retrograde signal that is necessary and sufficient for presynaptic differentiation.
108 CitationsSource
#1Haitao Wu (Georgia Regents University)H-Index: 9
#2Yisheng Lu (Georgia Regents University)H-Index: 13
Last. Lin Mei (Georgia Regents University)H-Index: 60
view all 7 authors...
Neuromuscular junction (NMJ) formation requires precise interaction between motoneurons and muscle fibers. LRP4 is a receptor of agrin that is thought to act in cis to stimulate MuSK in muscle fibers for postsynaptic differentiation. Here we dissected the roles of LRP4 in muscle fibers and motoneurons in NMJ formation by cell-specific mutation. Studies of muscle-specific mutants suggest that LRP4 is involved in deciding where to form AChR clusters in muscle fibers, postsynaptic differentiation, ...
93 CitationsSource
Cited By1
#1Courtney A. Burger (BCM: Baylor College of Medicine)H-Index: 1
#2Jonathan Alevy (BCM: Baylor College of Medicine)H-Index: 1
Last. Melanie A. Samuel (BCM: Baylor College of Medicine)H-Index: 2
view all 9 authors...
Structural changes in pre and postsynaptic neurons that accompany synapse formation often temporally and spatially overlap. Thus, it has been difficult to resolve which processes drive patterned connectivity. To overcome this, we use the laminated outer murine retina. We identify the serine/threonine kinase LKB1 as a key driver of synapse layer emergence. The absence of LKB1 in the retina caused a marked mislocalization and delay in synapse layer formation. In parallel, LKB1 modulated postsynapt...