Subject(s)
Corynebacterium Infections/diagnostic imaging , Kidney Pelvis/diagnostic imaging , Kidney Transplantation , Pyelitis/diagnostic imaging , Chronic Disease , Corynebacterium Infections/diagnosis , Corynebacterium Infections/drug therapy , Humans , Kidney Failure, Chronic/microbiology , Kidney Failure, Chronic/therapy , Kidney Transplantation/adverse effects , Male , Middle Aged , Opportunistic Infections/diagnosis , Opportunistic Infections/diagnostic imaging , Opportunistic Infections/drug therapy , Pyelitis/diagnosis , Pyelitis/drug therapy , Tomography, X-Ray Computed , Ureter/diagnostic imagingABSTRACT
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.
Subject(s)
Foot Deformities/genetics , Mutation/physiology , Peripheral Nervous System/growth & development , Peripheral Nervous System/physiology , Proteins/physiology , Amino Acid Sequence , Animals , Axons/physiology , Base Sequence , Cloning, Molecular , Coculture Techniques , DNA Transposable Elements , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Down-Regulation/genetics , Down-Regulation/physiology , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Genetic Complementation Test , Genotype , Immunohistochemistry , In Situ Hybridization , Lentivirus/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Myelin Sheath/physiology , Nerve Tissue Proteins , Neurons, Afferent/physiology , Phenotype , Proteins/genetics , RNA, Small Interfering/genetics , Rats , Reverse Transcriptase Polymerase Chain Reaction , Schwann Cells/physiology , TransfectionABSTRACT
Mice homozygous for the autosomal recessive mutation claw paw (clp) are characterized by limb posture abnormalities and congenital hypomyelination, with delayed onset of myelination of the peripheral nervous system but not the central nervous system. Although this combination of limb and peripheral nerve abnormalities in clp/clp mice might suggest a common neurogenic origin of the syndrome, it is not clear whether the clp gene acts primarily in the neurone, the Schwann cell or both. In the work described here, we address this question of cell autonomy of the clp mutation through reciprocal nerve grafting experiments between wild-type and clp/clp animals. Our results demonstrate that the clp mutation affects the Schwann cell compartment and possibly also the neuronal compartment. These data suggest that the clp gene product is expressed in Schwann cells as well as neurones and is likely to be involved in direct axon--Schwann cell interactions. Within the Schwann cell, clp affects a myelin-related signaling pathway that regulates periaxin and Krox-20 expression, but not Oct-6.
