Oscillations in notch signaling regulate maintenance of neural progenitors.
Expression of the Notch effector gene Hes1 is required for maintenance of neural progenitors in the embryonic brain, but persistent and high levels of Hes1 expression inhibit proliferation and differentiation of these cells. Here, by using a real-time imaging method, we found that Hes1 expression dynamically oscillates in neural progenitors. Furthermore, sustained overexpression of Hes1 downregulates expression of proneural genes, Notch ligands, and cell cycle regulators, suggesting that their proper expression depends on Hes1 oscillation. Surprisingly, the proneural gene Neurogenin2 (Ngn2) and the Notch ligand Delta-like1 (Dll1) are also expressed in an oscillatory manner by neural progenitors, and inhibition of Notch signaling, a condition known to induce neuronal differentiation, leads to downregulation of Hes1 and sustained upregulation of Ngn2 and Dll1. These results suggest that Hes1 oscillation regulates Ngn2 and Dll1 oscillations, which in turn lead to maintenance of neural progenitors by mutual activation of Notch signaling.
Shimojo
Hiromi
H
Institute for Virus Research, Kyoto University, and Japan Science and Technology Agency, CREST, Kyoto 606-8507, Japan.
Ohtsuka
Toshiyuki
T
Kageyama
Ryoichiro
R
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D001683:Biological Clocks / Q000502:physiology*; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011247:Pregnancy; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C512925:Dlk1 protein, mouse; C489734:Hes1 protein, mouse; C102938:Neurog2 protein, mouse