Rectification of muscle and nerve deficits in paralyzed ryanodine receptor type 1 mutant embryos

Locomotion and respiration require motor axon connectivity and activation of the neuromuscular junction (NMJ). Through a forward genetic screen for muscle weakness, we recently reported an allele of ryanodine receptor type 1 (Ryr1AG). Here we reveal a role for functional RyR1 during acetylcholine receptor (AChR) cluster formation and embryonic synaptic transmission. Ryr1AG homozygous embryos are non-motile. Motor axons extend past AChR clusters and enlarged AChR clusters are found under fasciculated nerves. Using physiological and pharmacological methods, we show that contractility can be resumed through the masking of a potassium leak, and evoked vesicular release can be resumed via bypassing the defect in RyR1 induced calcium release. Moreover, we show the involvement of ryanodine receptors in presynaptic release at the NMJ. This data provides evidence of a role for RyR1 on both the pre- and postsynaptic sides of the NMJ. •RyR1AG mice demonstrate structural and functional defects of the muscle and nerve.•Ryr1AG AChR clusters are larger than AChR clusters in wildtype muscle.•Ryr1AG/AG paralyzed diaphragms can contract through increased K+.•Ryr1AG/AG lack evoked transmitter release from the nerve.•Ryanodine receptors are involved in vesicular release of ACh at the NMJ.