Axons regulate the proliferation, survival and differentiation of Schwann cells. Neuregulin- I (NRG- 1), a family of neuronal growth factors, has an established and crucial role in the early events of Schwann cell development, promoting Schwann cell maturation, proliferation and survival. Neuregulin receptors, members of the erbB family of receptor tyrosine kinases, are expressed by Schwann cells. Following ligand binding, they undergo autophosphorylation and activate intracellular signaling pathways, notably investigator 3-kinase which we have shown is required for these early events. In this proposal, we will investigate whether NRG- 1 and the erbB receptors, exclusively mediate the initial interactions of axons and Schwann cells or whether they also mediate later interactions, including myelin and basal lamina (BL) and node of Ranvier formation. To investigate the role of NRG- 1 in these later events of development, we will coculture mature Schwann cells with neurons isolated from mice with either a conditional, neuron-specific knockout of NRG-1 or a knockout of the CRD-NRG-l isoform. We are particular interested in whether nrg- 1-I- neurons can still induce Schwann cell proliferation and survival and promote normal myelin and BL formation. We have recently found that erbB2 and several candidate interacting proteins, are enormously enriched in the Schwann cell microvilli which contact the nodal axolemma. To elucidate the signifance of this finding for local signaling and node organization, we will characterize the time course of its accumulation and its precise localization in the microvilli, determine whether erbB2 is complexed to and/or activates several candidate proteins in the microvilli and examine whether erbB2 regulates microvilli formation and nodal organization. Finally, we have found that MAP kinase and P1 3-kinase activation are activated not only during development, but also shortly after axotomy and NRG-induced demyelination. To investigate the role of MAP kinase and investigator 3-kinase activation during Wallerian degeneration and demyelination, we will examine whether activation of these pathways is a feature of demyelination in vivo, examine the effects of blocking their activation using pharmacologic inhibitors during Wallerian degeneration in vitro and determine whether the sequence of events during Wallenan degeneration is altered in cultures from NRG- 1 knockouts or in cultures treated with erbB2/e3rbB3-Fc, which inhibits NRG- 1 signaling.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Kleitman, Naomi
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
Zip Code
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