TY - JOUR
T1 - In vivo deletion of immunoglobulin domains 5 and 6 in Neurofascin (Nfasc) reveals domain-specific requirements in myelinated axons
AU - Thaxton, Courtney
AU - Pillai, Anilkumar M.
AU - Pribisko, Alaine L.
AU - Labasque, Marilyne
AU - Dupree, Jeffrey L.
AU - Faivre-Sarrailh, Catherine
AU - Bhat, Manzoor A.
PY - 2010/4/7
Y1 - 2010/4/7
N2 - The formation of paranodal axo-glial junctions is critical for the rapid and efficient propagation of nerve impulses. Genetic ablation of genes encoding the critical paranodal proteins Caspr, contactin (Cont), and the myelinating glia-specific isoform of Neurofascin (NfascNF155) results in the disruption of the paranodal axo-glial junctions, loss of ion channel segregation, and impaired nerve conduction, but the mechanisms regulating their interactions remain elusive. Here, we report that loss of immunoglobulin (Ig) domains 5 and 6 in NfascNF155 in mice phenocopies complete ablation of NfascNF155. The mutant mice lack paranodal septate junctions, resulting in the diffusion of Caspr and Cont from the paranodes, and redistribution of the juxtaparanodal potassium channels toward the nodes. Although critical for NfascNF155 function, we find that Ig5-6 are dispensable for nodal NfascNF186 function. Moreover, in vitro bindingassays using Ig5-6 deletion constructs reveal their importance for the association of NfascNF155 with Cont. These findings provide the first molecular evidence demonstrating domain-specific requirements controlling the association of the paranodal tripartite complex in vivo. Our studies further emphasize that in vivo structure/function analysis is necessary to define the unique protein-protein interactions that differentially regulate the functions of Neurofascins during axonal domain organization.
AB - The formation of paranodal axo-glial junctions is critical for the rapid and efficient propagation of nerve impulses. Genetic ablation of genes encoding the critical paranodal proteins Caspr, contactin (Cont), and the myelinating glia-specific isoform of Neurofascin (NfascNF155) results in the disruption of the paranodal axo-glial junctions, loss of ion channel segregation, and impaired nerve conduction, but the mechanisms regulating their interactions remain elusive. Here, we report that loss of immunoglobulin (Ig) domains 5 and 6 in NfascNF155 in mice phenocopies complete ablation of NfascNF155. The mutant mice lack paranodal septate junctions, resulting in the diffusion of Caspr and Cont from the paranodes, and redistribution of the juxtaparanodal potassium channels toward the nodes. Although critical for NfascNF155 function, we find that Ig5-6 are dispensable for nodal NfascNF186 function. Moreover, in vitro bindingassays using Ig5-6 deletion constructs reveal their importance for the association of NfascNF155 with Cont. These findings provide the first molecular evidence demonstrating domain-specific requirements controlling the association of the paranodal tripartite complex in vivo. Our studies further emphasize that in vivo structure/function analysis is necessary to define the unique protein-protein interactions that differentially regulate the functions of Neurofascins during axonal domain organization.
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U2 - 10.1523/JNEUROSCI.5951-09.2010
DO - 10.1523/JNEUROSCI.5951-09.2010
M3 - Article
C2 - 20371806
AN - SCOPUS:77950598241
SN - 0270-6474
VL - 30
SP - 4868
EP - 4876
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 14
ER -