The long term goal of this research program is to elucidate how axons drive Schwann cell ensheathment and myelination. We are investigating the role of neuregulin-1 (NRG1), a neuronal growth factor which regulates the entire Schwann cell lineage, including the binary choice between ensheathment and myelination in the PNS. The mechanisms by which type III NRG1 drives Schwann cell ensheathment and myelination remain poorly understood. NRG1 binds to erbB receptors on Schwann cells, activating the PI 3-kinase, PLC-3, and MAP kinase signaling pathways. Our general model is that Schwann cell survival, ensheathment and myelin wrapping all require NRG1-dependent activation of PI 3-kinase whereas other signaling pathways may drive the sequential expression of myelin-specific transcription factors (TFs). Using a recently generated transgenic mouse that expresses an activated, membrane targeted form of Akt1, we will investigate further how NRG1 drives axon ensheathment, myelination, and survival. Specifically, we will: i) investigate whether Akt is a primary effector of PI 3-kinase- dependent survival and ensheathment by analyzing mice deficient in Akt isoforms and by expressing activated Akt in Schwann cells interacting with NRG1 deficient neurons, ii) characterize the role(s) of the TORC1 and TORC2 pathways in ensheathment and myelination, and iii) analyze whether Akt cooperates with other signals, including NFAT, during myelination, by crossing transgenic mice expressing activated Akt and NFAT transgenes and examine potential cooperative effects on myelination. These studies should provide important insights into how type III NRG1 on the axon drives survival, ensheathment and myelination by Schwann cells. Relevance: These studies seek to identify signals that promote myelin sheath formation, the cellular insulation that surrounds nerve fibers and is critical for their proper function and long term integrity. Findings in this study may therefore have important implications for the pathogenesis of disorders of myelinated fibers, including neuropathies, and lead to new therapeutic strategies to promote their repair.
This project investigates the mechanisms by which type III Neuregulin 1 on the axon drives Schwann cell ensheathment and myelination, focusing in particular on the role of the PI 3- kinase pathway, and its effectors, in these events using myelinating cocultures and genetic mouse models.
|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|
|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|
|Taveggia, Carla; Thaker, Pratik; Petrylak, Ashley et al. (2008) Type III neuregulin-1 promotes oligodendrocyte myelination. Glia 56:284-93|
|Wang, Haibo; Tewari, Ambika; Einheber, Steven et al. (2008) Myosin II has distinct functions in PNS and CNS myelin sheath formation. J Cell Biol 182:1171-84|
|Zhang, Yueting; Taveggia, Carla; Melendez-Vasquez, Carmen et al. (2006) Interleukin-11 potentiates oligodendrocyte survival and maturation, and myelin formation. J Neurosci 26:12174-85|
|Taveggia, Carla; Zanazzi, George; Petrylak, Ashley et al. (2005) Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47:681-94|
|Gil, Orlando D; Zhang, Li; Chen, Suzanne et al. (2002) Complementary expression and heterophilic interactions between IgLON family members neurotrimin and LAMP. J Neurobiol 51:190-204|
|Chen, S; Gil, O; Ren, Y Q et al. (2001) Neurotrimin expression during cerebellar development suggests roles in axon fasciculation and synaptogenesis. J Neurocytol 30:927-37|
|Zanazzi, G; Einheber, S; Westreich, R et al. (2001) Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination. J Cell Biol 152:1289-99|
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