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

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.

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

“…1C). When crossed with a ubiquitous Cre driver line P Bi-2 -cre (32), the resulting constitutive Lrp4-deficient mice died perinatally, recapitulating the previously reported phenotype of Lrp4-null mice (17). Upon closer inspection, Lrp4 flox/flox ;P Bi-2 -cre animals exhibited polysyndactyly (Fig.…”

“…LRP4 has a well-recognized role in its interplay with agrin and muscle-specific kinase (MuSK) in the formation and stabilization of the neuromuscular junction (NMJ) (17)(18)(19), a synaptic connection that is required for communication between motor neurons and muscle fibers. Accordingly, Lrp4 loss-of-function results in perinatal lethality in mice due to breathing failure (17).…”

“…Accordingly, Lrp4 loss-of-function results in perinatal lethality in mice due to breathing failure (17). Moreover LRP4 loss-of-function mutations cause limb malformation, including syndactyly and synostosis, as well as renal agenesis in an autosomal-recessive fashion in Cenani-Lenz syndrome (CLS) [Online Mendelian Inheritance in Man (OMIM) 212780] (20-23) in human.…”

Neuronal LRP4 regulates synapse formation in the developing CNS

“…LRP4 levels influence the shape of dendritic arbors prior to affecting the density of dendritic spines Previous studies demonstrated that in Lrp4 −/− mice the α-motoneuron growth cone continues to grow along the muscle fiber and fails to develop into a presynaptic terminal (Weatherbee et al, 2006). As a consequence, axons with deficient capacity to establish synapses might become unusually long.…”

“…A key regulator for NMJ development is the low-density lipoprotein receptor-related protein 4 (LRP4; Weatherbee et al, 2006;Wu et al, 2012;Yumoto et al, 2012). At the NMJ, LRP4 forms a complex with the muscle-specific tyrosine kinase MuSK in the muscle fiber plasma membrane; this complex serves as the receptor for the motoneuron-derived extracellular matrix protein agrin (Kim et al, 2008;Zhang et al, 2008).…”