Postnatal Deletion of Numb/Numblike Reveals Repair and Remodeling Capacity in the Subventricular Neurogenic Niche

Howard Hughes Medical Institute, Departments of Physiology and Biochemistry, University of California, San Francisco, CA 94143, USA.
Cell (Impact Factor: 32.24). 01/2007; 127(6):1253-64. DOI: 10.1016/j.cell.2006.10.041
Source: PubMed


Neural stem cells are retained in the postnatal subventricular zone (SVZ), a specialized neurogenic niche with unique cytoarchitecture and cell-cell contacts. Although the SVZ stem cells continuously regenerate, how they and the niche respond to local changes is unclear. Here we generated nestin-creER(tm) transgenic mice with inducible Cre recombinase in the SVZ and removed Numb/Numblike, key regulators of embryonic neurogenesis from postnatal SVZ progenitors and ependymal cells. This resulted in severe damage to brain lateral ventricle integrity and identified roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival. Surprisingly, the ventricular damage was eventually repaired: SVZ reconstitution and ventricular wall remodeling were mediated by progenitors that escaped Numb deletion. Our results show a self-repair mechanism in the mammalian brain and may have implications for both niche plasticity in other areas of stem cell biology and the therapeutic use of neural stem cells in neurodegenerative diseases.

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Available from: Nenad Sestan, Jan 01, 2014
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    • "Neural stem cells (NSCs) reside in two regions of the adult mammalian forebrain: the subgranular zone in the dentate gyrus and the subventricular zone in the lateral wall of the lateral ventricle (SVZ). SVZ NSCs persist throughout adult life (Maslov et al., 2004; Molofsky et al., 2006; Imayoshi et al., 2008), giving rise primarily to neurons in the olfactory bulb as well as some astrocytes in the olfactory bulb (Lois and Alvarez-Buylla, 1994; Lois et al., 1996; Doetsch et al., 1999b; Ahn and Joyner, 2005; Kuo et al., 2006; Lagace et al., 2007; Merkle et al., 2007; Imayoshi et al., 2008; Chen et al., 2009) and oligodendrocytes in the corpus callosum and cortex (Nait-Oumesmar et al., 1999; Menn et al., 2006). In vivo, these NSCs are quiescent (Doetsch et al., 1999a; Pastrana et al., 2009), resistant to anti-mitotic agents (Morshead et al., 1994; Doetsch et al., 1999b, 2002; Giachino and Taylor, 2009), long-lived (Ahn and Joyner, 2005; Imayoshi et al., 2008), and capable of regenerating the SVZ after injury (Doetsch et al., 1999b, 2002; López-Juárez et al., 2013). "
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    ABSTRACT: Neurosphere formation is commonly used as a surrogate for neural stem cell (NSC) function but the relationship between neurosphere-initiating cells (NICs) and NSCs remains unclear. We prospectively identified, and isolated by flow cytometry, adult mouse lateral ventricle subventricular zone (SVZ) NICs as GlastmidEGFRhighPlexinB2highCD24−/lowO4/PSA-NCAM−/lowTer119/CD45− (GEPCOT) cells. They were highly mitotic and short-lived in vivo based on fate-mapping with Ascl1CreERT2 and Dlx1CreERT2. In contrast, pre-GEPCOT cells were quiescent, expressed higher Glast, and lower EGFR and PlexinB2. Pre-GEPCOT cells could not form neurospheres but expressed the stem cell markers Slc1a3-CreERT, GFAP-CreERT2, Sox2CreERT2, and Gli1CreERT2 and were long-lived in vivo. While GEPCOT NICs were ablated by temozolomide, pre-GEPCOT cells survived and repopulated the SVZ. Conditional deletion of the Bmi-1 polycomb protein depleted pre-GEPCOT and GEPCOT cells, though pre-GEPCOT cells were more dependent upon Bmi-1 for Cdkn2a (p16Ink4a) repression. Our data distinguish quiescent NSCs from NICs and make it possible to study their properties in vivo. DOI:
    eLife Sciences 05/2014; 3(3):e02669. DOI:10.7554/eLife.02669 · 9.32 Impact Factor
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    • "In our study, DCX staining may indicate neurogenesis. DCX-positive cells were found in contact with NSCs and structures participating in the neurogenesis process—namely the ependyma [48-51] and the circumventricular organs [20,52]. In spite of the controversies surrounding the topic, there is strong evidence that DCX is a marker for neurogenesis [44]. "
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    ABSTRACT: Prevailingly, adult mammalian neurogenesis is thought to occur in discrete, separate locations known as neurogenic niches that are best characterized in the subgranular zone (SGZ) of the dentate gyrus and in the subventricular zone (SVZ). The existence of adult human neurogenic niches is controversial. The existence of neurogenic niches was investigated with neurogenesis marker immunostaining in histologically normal human brains obtained from autopsies. Twenty-eight adult temporal lobes, specimens from limbic structures and the hypothalamus of one newborn and one adult were examined. The neural stem cell marker nestin stained circumventricular organ cells and the immature neuronal marker doublecortin (DCX) stained hypothalamic and limbic structures adjacent to circumventricular organs; both markers stained a continuous structure running from the hypothalamus to the hippocampus. The cell proliferation marker Ki-67 was detected predominately in structures that form the septo-hypothalamic continuum. Nestin-expressing cells were located in the fimbria-fornix at the insertion of the choroid plexus; ependymal cells in this structure expressed the putative neural stem cell marker CD133. From the choroidal fissure in the temporal lobe, a nestin-positive cell layer spread throughout the SVZ and subpial zone. In the subpial zone, a branch of this layer reached the hippocampal sulcus and ended in the SGZ (principally in the newborn) and in the subiculum (principally in the adults). Another branch of the nestin-positive cell layer in the subpial zone returned to the optic chiasm. DCX staining was detected in the periventricular and middle hypothalamus and more densely from the mammillary body to the subiculum through the fimbria-fornix, thus running through the principal neuronal pathway from the hippocampus to the hypothalamus. The column of the fornix forms part of this pathway and appears to coincide with the zone previously identified as the human rostral migratory stream. Partial co-labeling with DCX and the neuronal marker betaIII-tubulin was also observed. Collectively, these findings suggest the existence of an adult human neurogenic system that rises from the circumventricular organs and follows, at minimum, the circuitry of the hypothalamus and limbic system.
    Journal of Translational Medicine 03/2014; 12(1):75. DOI:10.1186/1479-5876-12-75 · 3.93 Impact Factor
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    • "The adult mammalian neurogenic niches show a remarkable capacity for self-repair and remodeling in response to lesion (Doetsch et al., 1999; Seri et al., 2001; Kuo et al., 2006; Nomura et al., 2010). However, neurogenesis declines with age in both the SVZ and SGZ (Lazarov et al., 2010) and most neuron subtypes produced in the OB are equally affected (Shook et al., 2012). "
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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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