Investigating endothelin receptor B signalling during myelination
View/ Open
Swire2017.pdf (3.965Mb)
Date
08/07/2017Item status
Restricted AccessEmbargo end date
31/12/2100Author
Swire, Matthew
Metadata
Abstract
A key process enabling the correct functioning of neural circuits involves the
formation of multi‐layered membranous myelin sheaths around axons. Myelin
sheaths, made by specialised glial cells called oligodendrocytes in the central
nervous system (CNS), metabolically support underlying axons and speed up
electrical impulse conduction, aiding efficient communication between neurons. As
only a subset of axons in the CNS are myelinated, with unique patterns developed
therein, it raises the questions: how does an oligodendrocyte choose which axon to
myelinate and what regulates the amount of myelin made?
The production of myelin sheaths by the oligodendrocyte, is under strong influence
from of a range of signals including those mediated by G protein‐coupled receptor
(GPR) superfamily members. One GPR, Endothelin receptor B (EDNRB), best
known for regulating blood flow, had previously been demonstrated to both
positively and negatively influence myelination.
I have investigated how EDNRB regulates myelination using an in vitro myelination
assay, alongside in vivo analysis in zebrafish and mice. These systems identified a
direct signalling role for EDNRB in the promotion of myelin sheath number.
Furthermore, profiling the protein signalling cascade downstream of this receptor
identified a range of known and novel factors involved in the regulation of myelin
sheath number including the MAPK pathway, Src family kinases, ErbB receptors,
protein kinase C ε, NMDAR and AMPAR. Functional analyses of a subset of these
factors elucidate how EDNRB signalling, potentially connecting signals from a
range of cell types, ensures correct adequate myelination in the CNS.