James Salzer, MD, PhD
CNS development and repair, myelination, neural stem cells
Stem cells, Myelination, nodes of Ranvier
Smilow Neuroscience Program
NYU School of Medicine
522 First Avenue
New York, NY 10016
Myelinated nerves form as the result of reciprocal interactions between axons and myelinating glia, i.e. Schwann cells in the PNS and oligodendrocytes in the CNS. Axons drive these glia to differentiate and form myelin, a membrane sheath that spirals around and protects axons. Myelin in turn, direct the reorganization of the axon into a series of specialized molecular domains, including nodes of Ranvier which are required for propagation of action potentials by saltatory conduction. Elucidation of the signaling between axons and glia is expected to provide important insights into the formation of myelinated nerves and the pathogenesis of neurologic disorders including Multiple Sclerosis and neuropathies in which these interactions are disrupted.
Our current studies focus on several key, related questions: i) how do axons drive glial cell differentiaion and myelination, ii) how do nodes of Ranvier assemble, iii) what causes glial cells to dedifferentiate during demyelinating disorders and iv) why is repair/remyelination in the adult CNS frequently ineffective? A long-standing project has been characterization of the role of the neuregulin family of growth factors on axons in promoting glial differentiation and myelination. Threshold levels of the type III isoform of neuregulin (NRG) 1 trigger Schwann cell myelination and determines the number of myelin wraps these glial cells make around axons. Type III NRG on the axon binds to members of the erbB receptor family on the glial cell thereby activating intracellular signaling pathways. We are currently investigating the pathways that regulate the transcriptional program and wrapping of Schwann cells around axons. In complementary studies, we are examining signaling pathways activated during demyelination, including genetic models of dysmyelinating neuropathies as candidate therapeutic targets.
We are also examining the assembly of the initial segment and nodes of Ranvier, sites of action potential initiation and regeneration, respectively. These domains contain high concentrations of voltage gated sodium and potassium channels in a multiprotein complex with cell adhesion molecules and a cytoskeletal scaffold. Current projects include analysis of trafficking of domain components to the node and studying node assembly in vivo using transgenic mice that express GFP-tagged proteins targeted to nodes.
Finally, we are investigating the contribution of stem cells and oligodendrocyte progenitors to remyelination of the adult CNS using genetic fate mapping strategies. We are examining cell autonomous signaling pathways that affect their ability to remyelinate and the effects of inflammation on the efficacy of remyelination.
- Zhang, Y., Y. Bekku, Y. Dzhashiashvili, S. Armenti, X. Meng, Y. Sasaki, J. Milbrandt, and Salzer J.L. (2012) Assembly and maintenance of nodes of Ranvier rely on distinct sources of proteins and targeting mechanisms. Neuron. 73:92-107. PMID: 22243749
- Marca RL, Cerri F, Horiuchi K, Bachi A, Feltri ML, Wrabetz L, Blobel CP, Quattrini A, Salzer JL, Taveggia C (2011) ADAM17/TACE inhibits Schwann cell myelination. Nature Neuroscience 14:857–865. PMID: 21666671
- Salzer JL (2008) Switching myelination on and off. J Cell Biol, 181:575-7. PMID: 18490509
- Salzer JL, Brophy PJ, Peles E (2008) Molecular domains of myelinated axons in the Peripheral Nervous System. Glia, 56: 1532-40. PMID: 18803321
- Dzhashiashvili Y, Zhang Y, Galinska J, Lam I, Grumet M,and Salzer JL(2007) Nodes of Ranvier and initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J Cell Biol, 177: 857-70. PMID: 17548513
- Maurel, P., Einheber, S., Thaker, P., Rubin, M, Murakami, Y, and Salzer J. L. (2007) The Nectin-like proteins mediate axo-glial interactions in the internode required for myelination. J Cell Biol, 178:861-874. PMID: 17724124