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Endosomal receptor trafficking and signal transduction in Schwann cells

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TitleInfo
Title
Endosomal receptor trafficking and signal transduction in Schwann cells
SubTitle
regulation of the Nrg1-induced PI3-kinase pathway
Name (type = personal)
NamePart (type = family)
Reddy
NamePart (type = given)
Kavya
NamePart (type = date)
1981-
DisplayForm
Kavya Reddy
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Bonder
NamePart (type = given)
Edward
DisplayForm
Edward Bonder
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Kim
NamePart (type = given)
Haesun
DisplayForm
Haesun Kim
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Friedman
NamePart (type = given)
Wilma
DisplayForm
Wilma Friedman
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Altan-Bonnet
NamePart (type = given)
Nihal
DisplayForm
Nihal Altan-Bonnet
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Wood
NamePart (type = given)
Teresa
DisplayForm
Teresa Wood
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - Newark
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2012
DateOther (qualifier = exact); (type = degree)
2012-10
CopyrightDate (qualifier = exact)
2012
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Neuregulin1-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.
Subject (authority = RUETD)
Topic
Biology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_4256
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
viii, 145 p. : ill.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = vita)
Includes vita
Note (type = statement of responsibility)
by Kavya Reddy
Subject (authority = ETD-LCSH)
Topic
Neuroglia
Subject (authority = ETD-LCSH)
Topic
Myelination
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10002600001.ETD.000066585
RelatedItem (type = host)
TitleInfo
Title
Graduate School - Newark Electronic Theses and Dissertations
Identifier (type = local)
rucore10002600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T31G0K25
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Reddy
GivenName
Kavya
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2012-09-20 14:38:03
AssociatedEntity
Name
Kavya Reddy
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - Newark
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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6650368
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application/pdf
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