Notch regulates cell fate and endrite morphology of newborn neurons in the postnatal dentate gyrus

Department of Neurobiology, Kavli Institute for Neuroscience, and Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(51):20558-63. DOI: 10.1073/pnas.0710156104
Source: PubMed


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.

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Available from: Joshua J Breunig, Nov 19, 2014
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    • "Ascl1 is not expressed by more mature cells in the lineage, including doublecortin (DCX) + neuroblasts and NeuN + granule neurons (Figure S1; data not shown). Together, these data agree with previous reports showing that Ascl1 expression is restricted to the earliest stages of the neurogenic lineage of the adult DG, including proliferating RGLs (Breunig et al., 2007; Kim et al., 2011) and early IPCs (Lugert et al., 2010, 2012), and that it is downregulated before IPCs begin to express neuronal markers and exit the cell cycle. "
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    • "During development Notch and Hes5 signaling drives neural pro - genitors into an astrocytic fate and regulates GFAP expression ( Breunig et al . , 2007 ; Chenn , 2009 ; Kanski et al . , 2013 ; Namihira et al . , 2009 ) . GFAP can in turn act as a suppressor of Notch signaling , creating a negative a negative feedback loop ( unpub - lished observations R . Kanski , E . M . Hol ) . It is therefore likely that Hes5 signaling may drive and / or maintain expression of vital astrocyte genes ,"
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    • "The activity of Notch target genes of the Hes/Hey family is fundamental for maintaining NSCs in an undifferentiated state, suppressing the expression of proneural genes including Ascl1 (Louvi and Artavanis-Tsakonas, 2006). Inhibition of Notch or RBP-J in adult NSCs results in NSC loss and impaired neurogenesis (Breunig et al., 2007; Andreu-Agullo et al., 2009; Ables et al., 2010; Aguirre et al., 2010; Chapouton et al., 2010; Ehm et al., 2010; Imayoshi et al., 2010; Lugert et al., 2010; Imayoshi and Kageyama, 2011). Canonical Notch signaling activity and Hes5 expression in particular distinguish NSCs from IPs in the developing and adult brain (Basak and Taylor, 2007; Mizutani et al., 2007; Andreu-Agullo et al., 2009; Imayoshi et al., 2010; Lugert et al., 2010; Giachino et al., 2014). "
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