Among γ-secretase substrates Notch1 alone is sufficient to block neurogenesis but does not confer self-renewal properties to neural stem cells.
Notch signaling pathway enhances neural stem cell characters and regulates cell fate decisions during neural development. Interestingly, besides Notch, other γ-secretase substrates such as APP, LRP2, and ErbB4 have also proven to have biological functions in neural development. We designed a unique experimental setting, combining gain-of- (expression of Notch intracellular domain, NICD) and loss-of-function (γ-secretase inhibition) methods, and were able to examine the function of Notch alone by excluding the activity of other γ-secretase substrates. Here, we show that the frequency and size of neurospheres generated from embryonic neural stem cells (NSCs) significantly decreased by 62.7% and 37.2%, respectively, in the presence of γ-secretase inhibitor even when NICD was expressed. Under the condition of differentiation, however, the γ-secretase inhibitor treatment did not influence the promotion of astrogenesis at the expense of neurogenesis by NICD. These results indicate that other γ-secretase substrate(s) along with Notch are important in the maintenance of the stemness of NSCs, but that Notch alone can sufficiently inhibit neurogenesis without the action of the other γ-secretase substrates during differentiation.
Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do 442-721, Republic of Korea.
Myung-Soon
MS
Yang
Jin-Su
JS
Hong
Seong-Tae
ST
Kim
Ki-Young
KY
Lee
Kye Won
KW
Park
Suk-Tae
ST
Kwon
Dae-Hyuk
DH
Kweon
Young Ho
YH
Koh
Nicholas
N
Gaiano
Keejung
K
Yoon
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases