Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination.
The adult subventricular zone (SVZ) is a potential source of precursor cells to replace neural cells lost during demyelination. To better understand the molecular events that regulate neural precursor cell responsiveness in this context we undertook a microarray and quantitative PCR based analysis of genes expressed within the SVZ during cuprizone-induced demyelination. We identified an up-regulation of the genes encoding bone morphogenic protein 4 (BMP4) and its receptors. Immunohistochemistry confirmed an increase in BMP4 protein levels and also showed an increase in phosphorylated SMAD 1/5/8, a key component of BMP4 signalling, during demyelination. In vitro analysis revealed that neural precursor cells isolated from demyelinated animals, as well as those treated with BMP4, produce more astrocytes. Similarly, there were increased numbers of astrocytes in vivo within the SVZ during demyelination. Intraventricular infusion of Noggin, an endogenous antagonist of BMP4, during cuprizone-induced demyelination reduced pSMAD1/5/8, decreased astrocyte numbers and increased oligodendrocyte numbers in the SVZ. Our results suggest that lineage commitment of SVZ neural precursor cells is altered during demyelination and that BMP signalling plays a role in this process.
Cate
Holly S
HS
Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia. hcate@unimelb.edu.au
Sabo
Jennifer K
JK
Merlo
Daniel
D
Kemper
Dennis
D
Aumann
Tim D
TD
Robinson
Julien
J
Merson
Toby D
TD
Emery
Ben
B
Perreau
Victoria M
VM
Kilpatrick
Trevor J
TJ
D000818:Animals; D000963:Antimetabolites; D001253:Astrocytes / Q000187:drug effects*; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D052004:Bone Morphogenetic Protein Receptors / Q000037:antagonists & inhibitors; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000276:immunology; D001973:Bromodeoxyuridine; D002352:Carrier Proteins / Q000494:pharmacology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000473:pathology*; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D042282:Microdissection; D008996:Monoamine Oxidase Inhibitors; D009836:Oligodendroglia / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099176:Noggin Protein
D000963:Antimetabolites; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins; D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D003471:Cuprizone; D008996:Monoamine Oxidase Inhibitors; D000099176:Noggin Protein