The long term goal of this research program is to identify the signals on axons that determine whether they are ensheathed or myelinated by Schwann cells and to elucidate the downstream pathways they activate in Schwann cell that regulate these distinct phenotypes. We have been characterizing the neuronal growth factor, neuregulin-1 (NRG1) in these events. NRG1 has three major isoforms (types I, II, and III), which differ in their amino terminal sequences and modes of signaling. Types I and II are paracrine signals that are shed from the axon surface by metalloproteinase cleavage whereas type III is a juxtacrine signal retained at the membrane. We have recently found that type III NRG1 levels provide the long sought instructive signal that determines the ensheathment fate of axons and does so by activating PI-kinase in Schwann cells, a key signaling pathway we have found to be essential for ensheathment and myelination. To elucidate how type NRG1, and PI-kinase, drives Schwann cell myelination and to examine its potential role in myelin maintenance, we are characterizing its function in a myelinating coculture system that faithfully replicates key events in the development of myelinating fibers in the PNS in vivo. In particular, we propose to: i) determine whether the type III NRG1 isoform is specific in promoting myelination or whether other NRG1 isoforms can substitute for its activity, whether its ability to trigger myelination requires that it be tethered to the axon, and the significance of its cleavage by metalloproteinases, ii) characterize which of the downstream effectors of PI-kinase are critical to its ability to promote Schwann cell ensheathment and myelination, and iii) determine whether NRG1 signals are required, not only during development, but also to maintain the integrity of the axon-myelinating Schwann cell unit in the adult. These studies should provide major insights into how the axon drives formation of the myelin sheath, which is essential for normal function of the nervous system. They are likely to have important implications for an understanding of the neurologic disability and pathogenesis of peripheral neuropathies, and of other disorders of myelinated fibers, and may lead to the development of new strategies to promote repair and remyelination of such disorders. ? ? ?
| Domènech-Estévez, Enric; Baloui, Hasna; Meng, Xiaosong et al. (2016) Akt Regulates Axon Wrapping and Myelin Sheath Thickness in the PNS. J Neurosci 36:4506-21 |
| Salzer, James L (2015) Schwann cell myelination. Cold Spring Harb Perspect Biol 7:a020529 |
| Samanta, Jayshree; Salzer, James L (2015) Myelination: actin disassembly leads the way. Dev Cell 34:129-30 |
| Samanta, Jayshree; Grund, Ethan M; Silva, Hernandez M et al. (2015) Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature 526:448-52 |
| Lim, Hyungsik; Sharoukhov, Denis; Kassim, Imran et al. (2014) Label-free imaging of Schwann cell myelination by third harmonic generation microscopy. Proc Natl Acad Sci U S A 111:18025-30 |
| Heller, Bradley A; Ghidinelli, Monica; Voelkl, Jakob et al. (2014) Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system. J Cell Biol 204:1219-36 |
| Zhu, Hong; Guariglia, Sara; Yu, Raymond Y L et al. (2013) Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol Biol Cell 24:1619-37, S1-3 |
| Salzer, James L (2012) Axonal regulation of Schwann cell ensheathment and myelination. J Peripher Nerv Syst 17 Suppl 3:14-9 |
| La Marca, Rosa; Cerri, Federica; Horiuchi, Keisuke et al. (2011) TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci 14:857-65 |
| Syed, Neeraja; Reddy, Kavya; Yang, David P et al. (2010) Soluble neuregulin-1 has bifunctional, concentration-dependent effects on Schwann cell myelination. J Neurosci 30:6122-31 |
Showing the most recent 10 out of 33 publications
