The claw paw mutation reveals a role for Lgi4 in peripheral nerve development

Abstract

Peripheral nerve development results from multiple cellular interactions between axons, Schwann cells and the surrounding mesenchymal tissue. The delayed axonal sorting and hypomyelination throughout the peripheral nervous system of claw paw (clp) mutant mice suggest that the clp gene product is critical for these interactions. Here we identify the clp mutation as a 225-bp insertion in the Lgi4 gene. Lgi4 encodes a secreted and glycosylated leucine-rich repeat protein and is expressed in Schwann cells. The clp mutation affects Lgi4 mRNA splicing, resulting in a mutant protein that is retained in the cell. Additionally, siRNA-mediated downregulation of Lgi4 in wild-type neuron-Schwann cell cocultures inhibits myelination, whereas exogenous Lgi4 restores myelination in clp/clp cultures. Thus, the abnormalities observed in clp mice are attributable to the loss of Lgi4 function, and they identify Lgi4 as a new component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…In addition, lipid biosynthesis genes are coordinately regulated, and the Srebp/Scap transcription factors and the control of their expression play important roles in lipid production (Verheijen et al, 2009;Norrmen et al, 2014). Extrinsic signals that trigger entry into myelination are provided by Nrg1/ErbB2/3, GPR126, integrins, extracellular matrix components and ADAM22/Lgi4 (Bermingham et al, 2006;Nave and Salzer, 2006;Ozkaynak et al, 2010;Taveggia et al, 2010;Raphael and Talbot, 2011). Thus, the Nrg1/ErbB2/3 system that regulates expansion of the progenitor pool and migration in early Schwann cell development is unexpectedly reused for myelination.…”

LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

“…Expression levels of these genes are generally low throughout the brain except in some distinctive areas: LGI2 is highly expressed in the pyriform cortex and the thalamic reticular nucleus; LGI3 in the facial nerve nucleus; and LGI4 in the purkinje cell layer of the cerebellar cortex and in the olfactory cortex [Senechal et al, 2005] and throughout the periferal nervous system (PNS) [Bermingham et al, 2006]. These specific areas of expression suggest that mutations in each of these paralogues could result in distinctly different neurological phenotypes.…”

“…These specific areas of expression suggest that mutations in each of these paralogues could result in distinctly different neurological phenotypes. Recently, the murine Lgi4 gene, which is expressed primarily by Schwann cells in the developing and mature PNS, has been found to carry a mutation in claw paw mutant mice, resulting in peripheral hypomyelination [Bermingham et al, 2006].…”

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

“…One recent success was the identification of Lgi4 as the affected gene in the mutant strain claw paw (Fig. 2b), demonstrating Lgi4's role in Schwann cell development [29]. Additionally, two mutant strains characterized by tetraparesis and early lethality have revealed a new link between mitochondrial function and peripheral nerve health.…”

“…The sprawling genetic defect was found in the cytoplasmic dynein heavy chain 1 gene (Dync1h1), demonstrating a new function for a gene previously linked to late-onset motor neuropathy. Reproduced with permission [29]. …”