Neuroprotection by NGF and BDNF against neurotoxin-exerted apoptotic death in neural stem cells are mediated through Trk receptors, activating PI3-kinase and MAPK pathways.
Neural stem cells (NSC) undergo apoptotic cell death during development of nervous system and in adult. However, little is known about the biochemical regulation of neuroprotection by neurotrophin in these cells. In this report, we demonstrate that Staurosporine (STS) and Etoposide (ETS) induced apoptotic cell death of NSC by a mechanism requiring Caspase 3 activation, poly (ADP-ribose) polymerase and Lamin A/C cleavage. Although C17.2 cells revealed higher mRNA level of p75 neurotrophin receptor (p75(NTR)) compared with TrkA or TrkB receptor, neuroprotective effect of both nerve growth factor (NGF) and brain-derived growth factor (BDNF) mediated through the activation of tropomyosin receptor kinase (Trk) receptors. Moreover, both NGF and BDNF induced the activation of the phosphatidylinositide 3 kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) pathway. Inhibition of Trk receptor by K252a reduced PARP cleavage as well as cell viability, whereas inhibition of p75(NTR) did not affect the effect of neurotrophin on neurotoxic insults. Thus our studies indicate that the protective effect of NGF and BDNF in NSC against apoptotic stimuli is mediated by the PI3K/Akt and MAPK signaling pathway via Trk receptors.
Nguyen
Nga
N
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Lee
Sang Bae
SB
Lee
Yun Song
YS
Lee
Yung Song
YS
Lee
Kyung-Hoon
KH
Ahn
Jee-Yin
JY
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D005047:Etoposide / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020932:Nerve Growth Factor / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D020917:Receptor, trkA / Q000096:biosynthesis / Q000502:physiology*; D020813:Receptor, trkB / Q000096:biosynthesis / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D015398:Signal Transduction; D019311:Staurosporine / Q000633:toxicity; D013234:Stem Cells / Q000502:physiology*; D015854:Up-Regulation
D019208:Brain-Derived Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D005047:Etoposide; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D019311:Staurosporine