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  1. Article ; Online: Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche.

    Fatt, Michael P / Tran, Lina M / Vetere, Gisella / Storer, Mekayla A / Simonetta, Jaclin V / Miller, Freda D / Frankland, Paul W / Kaplan, David R

    Stem cell reports

    2022  Volume 17, Issue 2, Page(s) 259–275

    Abstract: Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an ...

    Abstract Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs. This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.
    MeSH term(s) Aging ; Aniline Compounds/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Cellular Senescence/physiology ; Dentate Gyrus/cytology ; Dentate Gyrus/metabolism ; Female ; Hippocampus/cytology ; Male ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neurogenesis/drug effects ; Spatial Memory/drug effects ; Stem Cell Niche/physiology ; Sulfonamides/pharmacology
    Chemical Substances Aniline Compounds ; Sulfonamides ; navitoclax (XKJ5VVK2WD)
    Language English
    Publishing date 2022-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2021.12.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Conditional ablation of p63 indicates that it is essential for embryonic development of the central nervous system.

    Cancino, Gonzalo I / Fatt, Michael P / Miller, Freda D / Kaplan, David R

    Cell cycle (Georgetown, Tex.)

    2015  Volume 14, Issue 20, Page(s) 3270–3281

    Abstract: p63 is a member of the p53 family that regulates the survival of neural precursors in the adult brain. However, the relative importance of p63 in the developing brain is still unclear, since embryonic p63(-/-) mice display no apparent deficits in neural ... ...

    Abstract p63 is a member of the p53 family that regulates the survival of neural precursors in the adult brain. However, the relative importance of p63 in the developing brain is still unclear, since embryonic p63(-/-) mice display no apparent deficits in neural development. Here, we have used a more definitive conditional knockout mouse approach to address this issue, crossing p63(fl/fl) mice to mice carrying a nestin-CreERT2 transgene that drives inducible recombination in neural precursors following tamoxifen treatment. Inducible ablation of p63 following tamoxifen treatment of mice on embryonic day 12 resulted in highly perturbed forebrain morphology including a thinner cortex and enlarged lateral ventricles 3 d later. While the normal cortical layers were still present following acute p63 ablation, cortical precursors and neurons were both reduced in number due to widespread cellular apoptosis. This apoptosis was cell-autonomous, since it also occurred when p63 was inducibly ablated in primary cultured cortical precursors. Finally, we demonstrate increased expression of the mRNA encoding another p53 family member, ΔNp73, in cortical precursors of p63(-/-) but not tamoxifen-treated p63(fl/fl);R26YFP(fl/fl);nestin-CreERT2(+/Ø) embryos. Since ΔNp73 promotes cell survival, then this compensatory increase likely explains the lack of an embryonic brain phenotype in p63(-/-) mice. Thus, p63 plays a key prosurvival role in the developing mammalian brain.
    MeSH term(s) Animals ; Central Nervous System/embryology ; Central Nervous System/metabolism ; Embryonic Development/physiology ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neural Stem Cells/metabolism ; Neurogenesis/physiology ; Phosphoproteins/deficiency ; Phosphoproteins/genetics ; Pregnancy ; Trans-Activators/deficiency ; Trans-Activators/genetics
    Chemical Substances Phosphoproteins ; Trans-Activators ; Trp63 protein, mouse
    Language English
    Publishing date 2015-09-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.1080/15384101.2015.1087618
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5881: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Interleukin-6 Regulates Adult Neural Stem Cell Numbers during Normal and Abnormal Post-natal Development.

    Storer, Mekayla A / Gallagher, Denis / Fatt, Michael P / Simonetta, Jaclin V / Kaplan, David R / Miller, Freda D

    Stem cell reports

    2018  Volume 10, Issue 5, Page(s) 1464–1480

    Abstract: Circulating systemic factors can regulate adult neural stem cell (NSC) biology, but the identity of these circulating cues is still being defined. Here, we have focused on the cytokine interleukin-6 (IL-6), since increased circulating levels of IL-6 are ... ...

    Abstract Circulating systemic factors can regulate adult neural stem cell (NSC) biology, but the identity of these circulating cues is still being defined. Here, we have focused on the cytokine interleukin-6 (IL-6), since increased circulating levels of IL-6 are associated with neural pathologies such as autism and bipolar disorder. We show that IL-6 promotes proliferation of post-natal murine forebrain NSCs and that, when the IL-6 receptor is inducibly knocked out in post-natal or adult neural precursors, this causes a long-term decrease in forebrain NSCs. Moreover, a transient circulating surge of IL-6 in perinatal or adult mice causes an acute increase in neural precursor proliferation followed by long-term depletion of adult NSC pools. Thus, IL-6 signaling is both necessary and sufficient for adult NSC self-renewal, and acute perturbations in circulating IL-6, as observed in many pathological situations, have long-lasting effects on the size of adult NSC pools.
    MeSH term(s) Adult Stem Cells/cytology ; Adult Stem Cells/drug effects ; Adult Stem Cells/metabolism ; Animals ; Animals, Newborn ; Cell Count ; Cell Proliferation ; Growth and Development ; Interleukin-6/blood ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Interleukin-6/pharmacology ; Mice, Inbred C57BL ; Neural Stem Cells/cytology ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Neurogenesis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Interleukin-6/genetics ; Receptors, Interleukin-6/metabolism ; Time Factors
    Chemical Substances Interleukin-6 ; RNA, Messenger ; Receptors, Interleukin-6
    Language English
    Publishing date 2018-04-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2018.03.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Transient Maternal IL-6 Mediates Long-Lasting Changes in Neural Stem Cell Pools by Deregulating an Endogenous Self-Renewal Pathway

    Gallagher, Denis / Norman, Andreea A / Woodard, Cameron L / Yang, Guang / Gauthier-Fisher, Andrée / Fujitani, Masashi / Vessey, John P / Cancino, Gonzalo I / Sachewsky, Nadia / Woltjen, Knut / Fatt, Michael P / Morshead, Cindi M / Kaplan, David R / Miller, Freda D

    Cell stem cell. 2013 Nov. 7, v. 13, no. 5

    2013  

    Abstract: The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has ... ...

    Abstract The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has been implicated in cognitive disorders, might have long-lasting consequences for neural stem cell pools in adult progeny. We show that transient, maternally administered interleukin-6 (IL-6) resulted in an expanded adult forebrain neural precursor pool and perturbed olfactory neurogenesis in offspring months after fetal exposure. This increase is likely the long-term consequence of acute hyperactivation of an endogenous autocrine/paracrine IL-6-dependent self-renewal pathway that normally regulates the number of forebrain neural precursors. These studies therefore identify an IL-6-dependent neural stem cell self-renewal pathway in vivo, and support a model in which transiently increased maternal cytokines can act through this pathway in offspring to deregulate neural precursor biology from embryogenesis throughout life.
    Keywords adults ; cognition ; embryogenesis ; humans ; interleukin-6 ; models ; neurogenesis ; progeny ; stem cells
    Language English
    Dates of publication 2013-1107
    Size p. 564-576.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 2375354-7
    ISSN 1934-5909
    ISSN 1934-5909
    DOI 10.1016/j.stem.2013.10.002
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6589: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Zs.MG 75: Show issues

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  5. Article ; Online: p63 Regulates adult neural precursor and newly born neuron survival to control hippocampal-dependent Behavior.

    Cancino, Gonzalo I / Yiu, Adelaide P / Fatt, Michael P / Dugani, Chandrasagar B / Flores, Elsa R / Frankland, Paul W / Josselyn, Sheena A / Miller, Freda D / Kaplan, David R

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2013  Volume 33, Issue 31, Page(s) 12569–12585

    Abstract: The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 family member, in adult NPC function in mice. Conditional ablation ... ...

    Abstract The molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain adult neurogenesis, are not well defined. Here, we investigate the role of p63, a p53 family member, in adult NPC function in mice. Conditional ablation of p63 in adult NPCs or p63 haploinsufficiency led to reduced numbers of NPCs and newborn neurons in the neurogenic zones of the hippocampus and lateral ventricles and in the olfactory bulb. These reductions were attributable to enhanced apoptosis of NPCs and newborn neurons and were rescued by inhibition of caspase activity, p53, or the p53 apoptotic effector PUMA (p53-upregulated modulator of apoptosis). Moreover, these cellular deficits were functionally important because they led to perturbations in hippocampus-dependent memory formation. These results indicate that p63 regulates the numbers of adult NPCs and adult-born neurons as well as neural stem cell-dependent cognitive functions, and that it does so, at least in part, by inhibiting p53-dependent cell death.
    MeSH term(s) Adult Stem Cells/physiology ; Animals ; Bromodeoxyuridine/metabolism ; Cell Survival/drug effects ; Cell Survival/genetics ; Cell Survival/physiology ; Cells, Cultured ; Cerebral Ventricles/cytology ; Conditioning, Psychological/physiology ; Cues ; Exploratory Behavior/drug effects ; Exploratory Behavior/physiology ; Fear/psychology ; Hippocampus/physiology ; Intermediate Filament Proteins/genetics ; Maze Learning/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Nestin ; Neural Stem Cells/physiology ; Neurogenesis/drug effects ; Neurogenesis/genetics ; Neurogenesis/physiology ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Proteins/genetics ; RNA, Untranslated ; Tamoxifen/pharmacology ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcriptional Activation/drug effects ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Gt(ROSA)26Sor non-coding RNA, mouse ; Intermediate Filament Proteins ; Nerve Tissue Proteins ; Nes protein, mouse ; Nestin ; Phosphoproteins ; Proteins ; RNA, Untranslated ; Trans-Activators ; Trp63 protein, mouse ; Tumor Suppressor Protein p53 ; Tamoxifen (094ZI81Y45) ; Bromodeoxyuridine (G34N38R2N1)
    Language English
    Publishing date 2013-07-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.1251-13.2013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1668: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway.

    Gallagher, Denis / Norman, Andreea A / Woodard, Cameron L / Yang, Guang / Gauthier-Fisher, Andrée / Fujitani, Masashi / Vessey, John P / Cancino, Gonzalo I / Sachewsky, Nadia / Woltjen, Knut / Fatt, Michael P / Morshead, Cindi M / Kaplan, David R / Miller, Freda D

    Cell stem cell

    2013  Volume 13, Issue 5, Page(s) 564–576

    Abstract: The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has ... ...

    Abstract The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has been implicated in cognitive disorders, might have long-lasting consequences for neural stem cell pools in adult progeny. We show that transient, maternally administered interleukin-6 (IL-6) resulted in an expanded adult forebrain neural precursor pool and perturbed olfactory neurogenesis in offspring months after fetal exposure. This increase is likely the long-term consequence of acute hyperactivation of an endogenous autocrine/paracrine IL-6-dependent self-renewal pathway that normally regulates the number of forebrain neural precursors. These studies therefore identify an IL-6-dependent neural stem cell self-renewal pathway in vivo, and support a model in which transiently increased maternal cytokines can act through this pathway in offspring to deregulate neural precursor biology from embryogenesis throughout life.
    MeSH term(s) Animals ; Blotting, Western ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cell Line ; Cells, Cultured ; Female ; Humans ; Immunohistochemistry ; Interleukin-6/metabolism ; Interleukin-6/pharmacology ; Mice ; Neural Stem Cells/cytology ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Pregnancy ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Signal Transduction/genetics
    Chemical Substances Interleukin-6
    Language English
    Publishing date 2013-11-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2013.10.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6589: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 75: Show issues

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