Conservation of the Notch signalling pathway in mammalian neurogenesis.
The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.
de la Pompa
J L
JL
Amgen Institute, Toronto, Ontario, Canada. Jose.delaPompa@amgen.com
Wakeham
A
A
Correia
K M
KM
Samper
E
E
Brown
S
S
Aguilera
R J
RJ
Nakano
T
T
Honjo
T
T
Mak
T W
TW
Rossant
J
J
Conlon
R A
RA
D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000502:physiology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D004330:Drosophila; D005260:Female; D006720:Homozygote; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008322:Mammals; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis; D009420:Nervous System / Q000166:cytology / Q000196:embryology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C064045:delta protein