Notch promotes survival of neural precursor cells via mechanisms distinct from those regulating neurogenesis.
During development of the mammalian brain, many neural precursor cells (NPCs) undergo apoptosis. The regulation of such cell death, however, is poorly understood. We now show that the survival of mouse embryonic NPCs in vitro was increased by culture at a high cell density and that this effect was attributable to activation of Notch signaling. Expression of an active form of Notch1 thus markedly promoted NPC survival. Hes proteins, key effectors of Notch signaling in inhibition of neurogenesis, were not sufficient for the survival-promoting effect of Notch1. This effect of Notch1 required a region of the protein containing the RAM domain and was accompanied by up-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Moreover, knockdown of these proteins by RNA interference resulted in blockade of the Notch1-induced survival. These results reveal a new function of Notch, the promotion of NPC survival.
Oishi
Koji
K
Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
Kamakura
Sachiko
S
Isazawa
Yuko
Y
Yoshimatsu
Takeshi
T
Kuida
Keisuke
K
Nakafuku
Masato
M
Masuyama
Norihisa
N
Gotoh
Yukiko
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D005456:Fluorescent Dyes; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins; D015151:Immunoblotting; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011806:Quinolinium Compounds; D034622:RNA Interference; D051880:Receptors, Notch; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D013388:Succinimides; D015854:Up-Regulation
C492694:Alexa Fluor 488 carboxylic acid succinimidyl ester; C481052:Alexa fluor 546; D000911:Antibodies, Monoclonal; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D011806:Quinolinium Compounds; D051880:Receptors, Notch; D013388:Succinimides; D049452:Green Fluorescent Proteins; D008156:Luciferases