Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis

By Tomoko Kuwabara, Jenny Hsieh, Alysson Renato Muotri, Gene W. Yeo, M. Warashina, D. C. Lie, L. Moore, K. Nakashima, Makoto Asashima, Fred H. Gage. 2009

672 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement (2014, background): “…et al., 2012 GABA Neurotransmitter DG Ge et al., 2006 Glutamate Neurotransmitter SVZ Platel et al., 2010 WNT Morphogen DG Lie et al., 2005; Kuwabara et al., 2009 INTRACELLULAR FACTORS NFATc4 Transcription factor DG Quadrato et al., 2012 NF-KappaB p50 Transcription factor DG Denis-Donini…”
Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “For example, in animal models of Alzheimer’s disease, aberrant GABA signaling affects fate specification of neural progenitors and dendritic growth of newborn neurons in the aged SGZ (Li et al., 2009; Sun et al., 2009).”
Visualization and genetic manipulation of adult neurogenesis using transgenic mice (2011, background): “This mouse line has been useful in identification of the multipotent and self-renewal capacities of neural stem cells, their response to proneurogenic mechanisms, as well as implications of transcription factors in neurogenic pathways (Suh et al., 2007; Kuwabara et al., 2009).”
Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. (2016, positive): “Both transcription factors are direct targets of canonical Wnt signaling (Gao et al., 2009; Kuwabara et al., 2009).”
RBPJκ-Dependent Signaling Is Essential for Long-Term Maintenance of Neural Stem Cells in the Adult Hippocampus (2010, methodology): “Thus, EGFP reporter activity in both transgenic mouse lines consistently indicate that Notch signaling through RBPJ is active in Sox2-positive stem cells and that Notch signaling is inactivated in parallel with the loss of Sox2 expression, the initiation of NeuroD expression, and the neuronal fate c”
Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells (2010, background): “Although one study suggests that Wnt signaling can also promote cell proliferation in the DG [56], other publications clearly point out the function of the Wnt signaling pathway in activating neuronal differentiation during adult neurogenesis, and inhibiting this pathway results in hippocampus-depen”
The role of adult hippocampal neurogenesis in brain health and disease (2018, background): “Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, et al. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis.”
Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis (2011, background): “Interestingly, it has been recently shown that TCF/LEF sites and binding sites for the Sry-related HMG box (SOX) transcription factors often overlap, forming a SOX/LEF binding site (12), with the−43 kb site representing one of them.”
Emerging roles of Wnts in the adult nervous system (2010, background): “Recently, NEUROD1 , a pro-neurogenic transcription factor in the adult brain that is selectively expressed in dividing neural progenitors and in immature granule neurons in the adult dentate gyrus, was identified as a downstream effector of Wnts in adult neurogenesi”