Axon-glial interactions are critical for the induction of myelination and the domain organization of myelinated fibers. We recently reported that in the peripheral nervous system (PNS) neurons and myelinating Schwann cells express a new set of cell adhesion molecules called the Nectin-like (Necl) proteins. In particular, Necl-1 on axons mediates adhesion by specifically binding to Necl-4 on Schwann cells. We showed that Necl-4 is required to initiate PNS myelination. These results implicate the Necl proteins as new, crucial mediators of axon-glia interactions. A key question is how the Necl proteins, and in particular Necl-4, mediates Schwann cell myelination. The Necls mediate cell adhesion though their Ig-like extracellular domain, and interact with scaffolding intracellular proteins through a FERM- and PDZ-binding domains. Through these latter interactions the Necl proteins can assemble polarity and signaling complexes. In preliminary studies we have obtained evidence that Necl-4 interacts with the polarity protein Par-3. These studies have also pointed out a possible interaction (direct or indirect) between Necl-4 and the Schwann cell ErbB receptors that transduce the instructive, axon-derived myelinating signal. Using mutant versions of Necl-4 in combination with lentiviral knockdown/rescue strategies, in vivo an in vitro, we will characterize the requirement of the PDZ-binding domain of Necl-4 in the initial stages of Schwann cell myelination, address the functional significance of the Necl-4/Par-3 interaction, and investigate how Necl-4 influence ErbB receptor signaling. The overall goal of this project is to provide novel insights into the mechanisms that regulate myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies.

Public Health Relevance

The overall goal of this project is to provide novel insights into the mechanisms that regulate axon- glia interactions and myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065218-05
Application #
8897892
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Jakeman, Lyn B
Project Start
2011-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2017-08-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
Wu, Siliang; Chen, Ming-Shuo; Maurel, Patrice et al. (2018) Aligned fibrous PVDF-TrFE scaffolds with Schwann cells support neurite extension and myelination in vitro. J Neural Eng 15:056010
Heffernan, Corey; Jain, Mohit R; Liu, Tong et al. (2017) Nectin-like 4 Complexes with Choline Transporter-like Protein-1 and Regulates Schwann Cell Choline Homeostasis and Lipid Biogenesis in Vitro. J Biol Chem 292:4484-4498
Chen, Ming-Shuo; Kim, Hyosung; Jagot-Lacoussiere, LĂ©onard et al. (2016) Cadm3 (Necl-1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelination in vitro. Glia 64:2247-2262
Basak, Sayantani; Desai, Darshan J; Rho, Esther H et al. (2015) E-cadherin enhances neuregulin signaling and promotes Schwann cell myelination. Glia 63:1522-36