Metallothionein induces a regenerative reactive astrocyte phenotype via JAK/STAT and RhoA signalling pathways.
Following central nervous system injury, astrocytes rapidly respond by undergoing a stereotypical pattern of molecular and morphological alterations termed "reactive" astrogliosis. We have reported previously that metallothioneins (MTs) are rapidly expressed by reactive astrocytes and that their secretion and subsequent interaction with injured neurons leads to improved neuroregeneration. We now demonstrate that exogenous MT induces a reactive morphology and elevated GFAP expression in cultured astrocytes. Furthermore, these astrogliotic hallmarks were mediated via JAK/STAT and RhoA signalling pathways. However, rather than being inhibitory, MT induced a form of astrogliosis that was permissive to neurite outgrowth and which was associated with decreased chondroitin sulphate proteoglycan (CSPG) expression. The results suggest that MT has an important role in mediating permissive astrocytic responses to traumatic brain injury.
Leung
Y K J
YK
Menzies Research Institute, University of Tasmania, Private Bag 58, Tasmania, Australia.
Pankhurst
M
M
Dunlop
S A
SA
Ray
S
S
Dittmann
J
J
Eaton
E D
ED
Palumaa
P
P
Sillard
R
R
Chuah
M I
MI
West
A K
AK
Chung
R S
RS
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008668:Metallothionein / Q000172:deficiency / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology; D051381:Rats; D012038:Regeneration / Q000187:drug effects*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D011508:Chondroitin Sulfate Proteoglycans; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; C491054:Mt2 protein, mouse; D050791:STAT Transcription Factors; D053773:Transforming Growth Factor beta1; C525355:metallothionein-1, mouse; D008668:Metallothionein; D020742:rhoA GTP-Binding Protein