LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction

TLDR

Lrp4 is a single‑pass transmembrane protein expressed in multiple mouse tissues and essential for limb, organ, lung, and kidney development. The study demonstrates that Lrp4 is expressed at the muscle endplate and is necessary for neuromuscular synapse formation. Loss of Lrp4 causes perinatal lethality with severe presynaptic and postsynaptic defects, including abnormal motor axon branching, loss of acetylcholine receptor clustering, and failure of postsynaptic gene expression, indicating that Lrp4 acts in early, nerve‑independent steps of NMJ assembly and may be relevant to human neuromuscular disorders.

Abstract

Low-density lipoprotein receptor-related protein 4 (Lrp4) is a member of a family of structurally related, single-pass transmembrane proteins that carry out a variety of functions in development and physiology, including signal transduction and receptor-mediated endocytosis. Lrp4 is expressed in multiple tissues in the mouse, and is important for the proper development and morphogenesis of limbs, ectodermal organs, lungs and kidneys. We show that Lrp4 is also expressed in the post-synaptic endplate region of muscles and is required to form neuromuscular synapses. Lrp4-mutant mice die at birth with defects in both presynaptic and postsynaptic differentiation, including aberrant motor axon growth and branching, a lack of acetylcholine receptor and postsynaptic protein clustering, and a failure to express postsynaptic genes selectively by myofiber synaptic nuclei. Our data show that Lrp4 is required during the earliest events in postsynaptic neuromuscular junction (NMJ) formation and suggest that it acts in the early,nerveindependent steps of NMJ assembly. The identification of Lrp4 as a crucial factor for NMJ formation may have implications for human neuromuscular diseases such as myasthenia syndromes.