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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    ABSTRACT: The activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate of hippocampal stem cells, and inactivating Ascl1 blocks quiescence exit completely, rendering them unresponsive to activating stimuli. Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating the expression of cell-cycle regulatory genes. Ascl1 is similarly required for stem cell activation in the adult subventricular zone. Our results support a model whereby Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells.
    Neuron 09/2014; 83(5):1085–1097. DOI:10.1016/j.neuron.2014.08.004 · 15.05 Impact Factor
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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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    ABSTRACT: Reactive astrocytes and microglia are associated with amyloid plaques in Alzheimer's disease (AD). Yet, not much is known about the molecular alterations underlying this reactive phenotype. To get an insight into the molecular changes underlying AD induced astrocyte and microglia reactivity, we performed a transcriptional analysis on acutely isolated astrocytes and microglia from the cortex of aged controls and APPswe/PS1dE9 AD mice. As expected, both cell types acquired a proinflammatory phenotype, which confirms the validity of our approach. Interestingly, we observed that the immune alteration in astrocytes was relatively more pronounced than in microglia. Concurrently, our data reveal that astrocytes display a reduced expression of neuronal support genes and genes involved in neuronal communication. The microglia showed a reduced expression of phagocytosis and/or endocytosis genes. Co-expression analysis of a human AD expression data set and the astrocyte and microglia data sets revealed that the inflammatory changes in astrocytes were remarkably comparable in mouse and human AD, whereas the microglia changes showed less similarity. Based on these findings we argue that chronically proinflammatory astrocyte and microglia phenotypes, showing a reduction of genes involved in neuronal support and neuronal signaling, are likely to contribute to the neuronal dysfunction and cognitive decline in AD.
    Neurobiology of Aging 06/2014; 35(12). DOI:10.1016/j.neurobiolaging.2014.06.004 · 5.01 Impact Factor
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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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    ABSTRACT: Adult neural stem cells (NSCs) are perceived as a homogeneous population of cells that divide infrequently and are capable of multi-lineage differentiation. However, recent data revealed that independent stem cell lineages act in parallel to maintain neurogenesis and provide a cellular source for tissue repair. In addition, even within the same lineage, the stem and progenitor cells are strikingly heterogeneous including NSCs that are dormant or mitotically active. We will discuss these different NSC populations and activity states with relation to their role in neurogenesis and regeneration but also how these different stem cells respond to aging. NSCs depend on Notch signaling for their maintenance. While Notch-dependence is a common feature among NSC populations, we will discuss how differences in Notch signaling might contribute to adult NSC heterogeneity. Understanding the fate of multiple NSC populations with distinct functions has implications for the mechanisms of aging and regeneration.
    Frontiers in Neuroscience 02/2014; 8(8):32. DOI:10.3389/fnins.2014.00032 · 3.66 Impact Factor
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