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Mechanical trauma induces rapid astroglial activation of ERK/MAP kinase: Evidence for a paracrine signal
Author(s) -
Mandell James W.,
Gocan Nigel C.,
Vandenberg Scott R.
Publication year - 2001
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.1062
Subject(s) - mapk/erk pathway , astrogliosis , microbiology and biotechnology , astrocyte , biology , kinase , protein kinase a , signal transduction , neuroscience , central nervous system
Astrogliosis is a prominent and ubiquitous reaction of astrocytes to many forms of CNS injury, often implicated in the poor regenerative capacity of the adult mammalian CNS. Transmembrane signals that rapidly trigger and maintain astroglial responses to injury are largely undefined. Several candidate inducers of astrogliosis, including growth factors and neuropeptides, act via the extracellular signal‐regulated kinase (ERK)/mitogen‐activated protein kinase (MAPK) pathway. We previously observed chronically activated ERK/MAPK in human reactive astrocytes. To investigate mechanisms of pathway activation in a defined in vitro model, primary cultured astroglial monolayers were subjected to focal mechanical injury. Within 2–10 min, ERK/MAPK was activated, but only in cells near the wound edge. By 30 min, the entire monolayer showed activation, which persisted for 4 to 8 h. ERK/MAPK activation was specifically blocked by application of the MEK inhibitors, PD98059 and U0126. Cell‐cell contact was not necessary for intercellular spread of ERK/MAPK activation, and ERK/MAPK‐stimulating activity was found in the injury‐conditioned medium. The activating factor was shown to have a native size of 50–100 kD and did not signal through the classical EGF receptor. Injury‐induced signaling to ERK/MAPK required Ras, as demonstrated by specific blockade after transient transfection with a dominant negative Ha‐RasN17 construct. Finally, we demonstrated that focal lesioning of adult rat cortex induces a rapid activation and spreading of astroglial ERK/MAPK, suggesting that similar mechanisms may operate in astroglial activation following acute brain injury. GLIA 34:283–295, 2001. © 2001 Wiley‐Liss, Inc.