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Necl‐4/Cadm4 recruits Par‐3 to the Schwann cell adaxonal membrane
Author(s) -
Meng Xiaosong,
Maurel Patrice,
Lam Isabel,
Heffernan Corey,
Stiffler Michael A.,
McBeath Gavin,
Salzer James L.
Publication year - 2019
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23578
Subject(s) - pdz domain , biology , microbiology and biotechnology , schwann cell , axon , cytoplasm , cell polarity , membrane protein , node of ranvier , pseudopodia , cell membrane , myelin , cell , biochemistry , membrane , neuroscience , central nervous system , actin
Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon‐Schwann cell interactions are mediated by the Nectin‐like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl‐1/Cadm3 expressed on the axon surface binds to Necl‐4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl‐4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl‐4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl‐4 contains a PDZ‐domain binding motif. Accordingly, we used the CTR of Necl‐4 in an unbiased proteomic screen of PDZ‐domain proteins. We identify Par‐3, a multi‐PDZ domain containing protein of the Par‐aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl‐4 and Par‐3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl‐4 binds to the first PDZ domain of Par‐3 thereby recruiting Par‐3 to sites of Necl‐4/Necl‐1 interaction. Knockdown of Necl‐4 perturbs Par‐3 localization to the inner membrane of Schwann cells in myelinating co‐cultures. These findings implicate interactions of Necl‐1/Necl‐4 in the recruitment of Par‐3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.