Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells.
Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jkappa, a key molecule in Notch signaling, by using RBP-Jkappa(-/-) embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains of RBP-Jkappa(-/-) or Notch1(-/-) mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1(+/-) adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.
Hitoshi
Seiji
S
Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. shitoshi-tky@umin.ac.jp
Alexson
Tania
T
Tropepe
Vincent
V
Donoviel
Dorit
D
Elia
Andrew J
AJ
Nye
Jeffrey S
JS
Conlon
Ronald A
RA
Mak
Tak W
TW
Bernstein
Alan
A
van der Kooy
Derek
D
D000818:Animals; D001921:Brain / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002454:Cell Differentiation; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1; D016548:Prosencephalon / Q000378:metabolism; D011485:Protein Binding; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors
D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; D001973:Bromodeoxyuridine