Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus.
The lifelong addition of neurons to the hippocampus is a remarkable form of structural plasticity, yet the molecular controls over proliferation, neuronal fate determination, survival, and maturation are poorly understood. Expression of Notch1 was found to change dynamically depending on the differentiation state of neural precursor cells. Through the use of inducible gain- and loss-of-function of Notch1 mice we show that this membrane receptor is essential to these distinct processes. We found in vivo that activated Notch1 overexpression induces proliferation, whereas gamma-secretase inhibition or genetic ablation of Notch1 promotes cell cycle exit, indicating that the level of activated Notch1 regulates the magnitude of neurogenesis from postnatal progenitor cells. Abrogation of Notch signaling in vivo or in vitro leads to a transition from neural stem or precursor cells to transit-amplifying cells or neurons. Further, genetic Notch1 manipulation modulates survival and dendritic morphology of newborn granule cells. These results provide evidence for the expansive prevalence of Notch signaling in hippocampal morphogenesis and plasticity, suggesting that Notch1 could be a target of diverse traumatic and environmental modulators of adult neurogenesis.
Breunig
Joshua J
JJ
Department of Neurobiology, Kavli Institute for Neuroscience, and Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Silbereis
John
J
Vaccarino
Flora M
FM
Sestan
Nenad
N
Rakic
Pasko
P
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D003712:Dendrites / Q000648:ultrastructure*; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development*; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D051881:Receptor, Notch1; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases