IGF-1 receptor-mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus.
Adult progenitor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus is a dynamic process that is modulated by an array of physiological process, including locomotor activity and novel environmental stimuli. In addition, pathophysiological events, such as ischemia and status epilepticus (SE), have been shown to stimulate neurogenesis. Currently, limited information is available regarding the extracellular stimuli, receptors, and downstream intracellular effectors that couple excitotoxic stimulation to progenitor cell proliferation. Here we show that pilocarpine-induced SE triggers a set of signaling events that impinge upon the p42/44 mitogen-activated protein kinase (MAPK) pathway to drive progenitor cell proliferation in the SGZ at 2-days post-SE. Increased proliferation was dependent on insulin-like growth factor-1 (IGF-1), which was localized to activated microglia near the SGZ. Using a combination of techniques, we show that IGF-1 is a CREB-regulated gene and that SE triggered CRE-dependent transcription in microglia at 2-days post-SE. Together, these data identify a potential signaling program that couples SE to progenitor cell proliferation. SE triggers CREB-dependent transcription in reactive microglia. As a CREB-target gene, IGF-1 expression is upregulated, and by 2-days post-SE, IGF-1 triggers MAPK pathway activation in progenitor cells and, in turn, an increase in progenitor cell proliferation.
Choi
Yun-Sik
YS
Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
Cho
Hee-Yeon
HY
Hoyt
Kari R
KR
Naegele
Janice R
JR
Obrietan
Karl
K
D000818:Animals; D018929:Cell Culture Techniques; D002455:Cell Division; D018891:Dentate Gyrus / Q000502:physiology / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction; D013226:Status Epilepticus / Q000503:physiopathology*; D013234:Stem Cells / Q000166:cytology* / Q000473:pathology
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases