Neurogenesis response to hypoxia-induced cell death: map kinase signal transduction mechanisms.
Hypoxic stress induces apoptosis of hippocampal CA1 neurons while selectively sparing those in CA2-3. Proliferation and differentiation of local stem cells may potentially replace lost neurons. We examined MAP kinase signaling regulation of these dual responses. Rat organotypic hippocampal cultures were exposed to hypoxia for up to 6 h followed by reoxygenation. JNKs and ERKs were maximally activated by 4 h, returning approximately to basal levels by 6 h. Apoptosis of CA1 neurons was maximal by 6-h hypoxia, although JNK activation had returned to basal levels. A neuroprotective protein, JNK-interacting protein 1 (JIP1), an inhibitor of JNK-mediated apoptosis, was reduced by 6-h hypoxia and markedly decreased by 24-h reoxygenation in CA1 neurons as was DENN/MADD, which also modulates JNK-mediated cell death. A second peak of ERK1 activation occurred at 24-h reoxygenation and declined to control levels by 48 h. Stem cells were detected by antinestin and cell proliferation confirmed with anti-PCNA immunohistochemistry and BrdU incorporation. With U0126, an inhibitor of ERK activation, BrdU labeling was strikingly reduced implicating ERKs in the proliferation response. Antidoublecortin (DCX), which detects neural progenitor cells, colabeled a subset of BrdU-positive cells that extended from the dentate granule neurons into CA1. Astrocytes were colabeled with BrdU. Thus, hypoxia concurrently triggered both JNK and ERK signaling, and with reoxygenation, ERK1 activation and stem cell proliferation followed by neuronal progenitor cell differentiation and targeted migration to the site of pyramidal neuronal loss.
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Li
L
Zhou
Keith
K
Del Villar
Zhaohui
Z
Dong
Carol A
CA
Miller
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000473:pathology / Q000502:physiology*; D002534:Hypoxia, Brain / Q000378:metabolism / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen