Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis.
In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.
Kuwabara
Tomoko
T
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Science City, Japan. t.warashina@aist.go.jp
Hsieh
Jenny
J
Muotri
Alysson
A
Yeo
Gene
G
Warashina
Masaki
M
Lie
Dieter Chichung
DC
Moore
Lynne
L
Nakashima
Kinichi
K
Asashima
Makoto
M
Gage
Fred H
FH
D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D055748:SOXB1 Transcription Factors; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C501008:Neurod1 protein, mouse; C527783:Sox2 protein, mouse
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