Neuromuscular synaptic patterning requires the function of skeletal muscle dihydropyridine receptors

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2011; 14(5):570-7. DOI: 10.1038/nn.2792
Source: PubMed


Developing skeletal myofibers in vertebrates are intrinsically 'pre-patterned' for motor nerve innervation. However, the intrinsic factors that regulate muscle pre-patterning remain unknown. We found that a functional skeletal muscle dihydropyridine receptor (DHPR, the L-type Ca(2+) channel in muscle) was required for muscle pre-patterning during the development of the neuromuscular junction (NMJ). Targeted deletion of the β1 subunit of DHPR (Cacnb1) in mice led to muscle pre-patterning defects, aberrant innervation and precocious maturation of the NMJ. Reintroducing Cacnb1 into Cacnb1(-/-) muscles reversed the pre-patterning defects and restored normal development of the NMJ. The mechanism by which DHPRs govern muscle pre-patterning is independent of their role in excitation-contraction coupling, but requires Ca(2+) influx through the L-type Ca(2+) channel. Our findings indicate that the skeletal muscle DHPR retrogradely regulates the patterning and formation of the NMJ.

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    • "A large number of studies have advanced our understanding of the early events in nervemuscle synaptogenesis, but the molecular mechanisms for maintaining these synapses remain largely obscure. For example, nerve independent prepatterning, the earliest stage of synapse formation, requires MuSK, rapsyn, Dok7, LRP4, Wnt11r and functional DHPR Ca channels (Kim et al., 2008; Zhang et al., 2008; Jing et al., 2009; Chen et al., 2011). Agrin, MuSK, LRP4 and neural activity collaborate during the subsequent prenatal differentiation of the synapse (Witzemann, 2006; Wu et al., 2010). "
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