Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging.
New neurons are generated in the adult hippocampus throughout life by neural stem/progenitor cells (NSCs), and neurogenesis is a plastic process responsive to external stimuli. We show that canonical Notch signaling through RBP-J is required for hippocampal neurogenesis. Notch signaling distinguishes morphologically distinct Sox2(+) NSCs, and within these pools subpopulations can shuttle between mitotically active or quiescent. Radial and horizontal NSCs respond selectively to neurogenic stimuli. Physical exercise activates the quiescent radial population whereas epileptic seizures induce expansion of the horizontal NSC pool. Surprisingly, reduced neurogenesis correlates with a loss of active horizontal NSCs in aged mice rather than a total loss of stem cells, and the transition to a quiescent state is reversible to rejuvenate neurogenesis in the brain. The discovery of multiple NSC populations with Notch dependence but selective responses to stimuli and reversible quiescence has important implications for the mechanisms of adaptive learning and also for regenerative therapy.
Lugert
Sebastian
S
Department of Molecular Embryology, Max Planck Institute of Immunobiology, Stubeweg 51, D-79108 Freiburg, Germany.
Basak
Onur
O
Knuckles
Philip
P
Haussler
Ute
U
Fabel
Klaus
K
Götz
Magdalena
M
Haas
Carola A
CA
Kempermann
Gerd
G
Taylor
Verdon
V
Giachino
Claudio
C
D000375:Aging / Q000473:pathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D048430:Cell Shape; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D051379:Mice; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010805:Physical Conditioning, Animal; D051880:Receptors, Notch / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C489685:Hes5 protein, mouse; C527783:Sox2 protein, mouse