TitleEndosomal receptor trafficking and signal transduction in Schwann cells
NameReddy, Kavya (author), Bonder, Edward (chair), Kim, Haesun (internal member), Friedman, Wilma (internal member), Altan-Bonnet, Nihal (internal member), Wood, Teresa (outside member), Rutgers University, Graduate School - Newark,
DescriptionNeuregulin1-ErbB signaling is important for various functions during Schwann cell development and myelination. Activation of the ErbB receptors also triggers myelin breakdown in mature myelinating Schwann cells. The mechanism by which the activated ErbB receptor complex elicits multiple biological functions in Schwann cells is unclear. In Charcot-Marie-Tooth (CMT) disease - the most common demyelinating neuropathy in the peripheral nervous system - many proteins involved in regulating intracellular vesicular trafficking and sorting through the endocytic pathway are found mutated. Endocytic pathways are also strongly implicated in the regulation of signal transduction by cell surface receptors. It is possible that aberrant regulation of the ErbB receptors and downstream signal activation by the impaired endocytic components contribute to the disease manifestation. The function of ErbB receptor trafficking and signal modulation in Schwann cells is largely unknown. We hypothesized that Nrg1-induced ErbB2 and ErbB3 receptor trafficking can differentially regulate signaling by spatially and temporally localizing receptors in different endocytic compartments. In this study, we show that following treatment with soluble Nrg1, internalized ErbB receptors are sorted into the late endosome/lysosome for degradation or transported to the recycling endosome and reappear on the cell surface. ErbB receptor recycling is also regulated by Nrg1 dose. Inhibition of receptor endocytosis by impairing dynamin activity blocked the Nrg1-induced Akt activation and abrogated the pro-myelinating effect in co-cultures. Interestingly, allowing receptor endocytosis but inhibiting the subsequent recycling from the early endosome enhanced Akt activation, indicating the importance of the early endosomal signaling for the Nrg1-induced Akt activity. Supporting this, sub-cellular fractionation showed that active Akt was enriched in the endosomal fraction in Schwann cells. We also investigated the mechanism by which membrane-bound Nrg1 Type III regulates ErbB receptor trafficking in Schwann cells. Binding of the axonal Nrg1 induced both ErbB2 and ErbB3 downregulation indicating receptor internalization. The membrane-bound Nrg1 Type III was also internalized into the Schwann cells, appearing in Rab5-positive early endosomes. The Nrg1-induced Akt activation, which is necessary for myelination was abrogated when receptor endocytosis in Schwann cells was blocked. Our results show that endocytic trafficking is important for the pro-myelinating function of Nrg1. The results also suggest that impaired endocytic pathways may contribute to the development of demyelinating neuropathy by resulting in aberrant regulation of the Nrg1-ErbB signaling in Schwann cells.
NoteIncludes bibliographical references
Noteby Kavya Reddy
CollectionGraduate School - Newark Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.