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  1. Article ; Online: Dopamine signaling from ganglion cells directs layer-specific angiogenesis in the retina.

    Liang, Justine H / Akhanov, Viktor / Ho, Anthony / Tawfik, Mohamed / D'Souza, Shane P / Cameron, Morven A / Lang, Richard A / Samuel, Melanie A

    Current biology : CB

    2023  Volume 33, Issue 18, Page(s) 3821–3834.e5

    Abstract: During central nervous system (CNS) development, a precisely patterned vasculature emerges to support CNS function. How neurons control angiogenesis is not well understood. Here, we show that the neuromodulator dopamine restricts vascular development in ... ...

    Abstract During central nervous system (CNS) development, a precisely patterned vasculature emerges to support CNS function. How neurons control angiogenesis is not well understood. Here, we show that the neuromodulator dopamine restricts vascular development in the retina via temporally limited production by an unexpected neuron subset. Our genetic and pharmacological experiments demonstrate that elevating dopamine levels inhibits tip-cell sprouting and vessel growth, whereas reducing dopamine production by all retina neurons increases growth. Dopamine production by canonical dopaminergic amacrine interneurons is dispensable for these events. Instead, we found that temporally restricted dopamine production by retinal ganglion cells (RGCs) modulates vascular development. RGCs produce dopamine precisely during angiogenic periods. Genetically limiting dopamine production by ganglion cells, but not amacrines, decreases angiogenesis. Conversely, elevating ganglion-cell-derived dopamine production inhibits early vessel growth. These vasculature outcomes occur downstream of vascular endothelial growth factor receptor (VEGFR) activation and Notch-Jagged1 signaling. Jagged1 is increased and subsequently inhibits Notch signaling when ganglion cell dopamine production is reduced. Our findings demonstrate that dopaminergic neural activity from a small neuron subset functions upstream of VEGFR to serve as developmental timing cue that regulates vessel growth.
    MeSH term(s) Dopamine/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Retina ; Retinal Ganglion Cells/metabolism ; Signal Transduction
    Chemical Substances Dopamine (VTD58H1Z2X) ; Vascular Endothelial Growth Factor A
    Language English
    Publishing date 2023-08-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2023.07.040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss.

    Chronowski, Christopher / Akhanov, Viktor / Chan, Doug / Catic, Andre / Finegold, Milton / Sahin, Ergün

    Metabolites

    2021  Volume 11, Issue 6

    Abstract: Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, ...

    Abstract Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, increased apoptosis, and senescence, despite lower hepatic fat accumulation in TKO mice compared to wild type mice with long telomeres. The decreased fat accumulation in TKO is mediated by p53 and deletion of p53 normalizes hepatic fat content but also causes polyploidy, polynuclearization, dysplasia, cell death, and liver damage. Together, these studies suggest that liver tissue with short telomers are highly susceptible to fructose and respond with p53 activation and liver damage that is further exacerbated when p53 is lost resulting in dysplastic changes.
    Language English
    Publishing date 2021-06-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662251-8
    ISSN 2218-1989
    ISSN 2218-1989
    DOI 10.3390/metabo11060394
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Rapid 3D-STORM imaging of diverse molecular targets in tissue.

    Albrecht, Nicholas E / Jiang, Danye / Akhanov, Viktor / Hobson, Robert / Speer, Colenso M / Robichaux, Michael A / Samuel, Melanie A

    Cell reports methods

    2022  Volume 2, Issue 7, Page(s) 100253

    Abstract: Fine-scale molecular architecture is critical for nervous system and other biological functions. Methods to visualize these nanoscale structures would benefit from enhanced accessibility, throughput, and tissue compatibility. Here, we report RAIN-STORM, ... ...

    Abstract Fine-scale molecular architecture is critical for nervous system and other biological functions. Methods to visualize these nanoscale structures would benefit from enhanced accessibility, throughput, and tissue compatibility. Here, we report RAIN-STORM, a rapid and scalable nanoscopic imaging optimization approach that improves three-dimensional visualization for subcellular targets in tissue at depth. RAIN-STORM uses conventional tissue samples and readily available reagents and is suitable for commercial instrumentation. To illustrate the efficacy of RAIN-STORM, we utilized the retina. We show that RAIN-STORM imaging is versatile and provide 3D nanoscopic data for over 20 synapse, neuron, glia, and vasculature targets. Sample preparation is also rapid, with a 1-day turnaround from tissue to image, and parameters are suitable for multiple tissue sources. Finally, we show that this method can be applied to clinical samples to reveal nanoscale features of human cells and synapses. RAIN-STORM thus paves the way for high-throughput studies of nanoscopic targets in tissue.
    MeSH term(s) Humans ; Microscopy, Fluorescence ; Imaging, Three-Dimensional ; Neurons ; Neuroglia ; Synapses
    Language English
    Publishing date 2022-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2667-2375
    ISSN (online) 2667-2375
    DOI 10.1016/j.crmeth.2022.100253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Kctd7 deficiency induces myoclonic seizures associated with Purkinje cell death and microvascular defects.

    Liang, Justine H / Alevy, Jonathan / Akhanov, Viktor / Seo, Ryan / Massey, Cory A / Jiang, Danye / Zhou, Joy / Sillitoe, Roy V / Noebels, Jeffrey L / Samuel, Melanie A

    Disease models & mechanisms

    2022  Volume 15, Issue 9

    Abstract: Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental ... ...

    Abstract Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. KCTD7-driven disease is part of a large family of progressive myoclonic epilepsy syndromes displaying a broad spectrum of clinical severity. Animal models of KCTD7-related disease are lacking, and little is known regarding how KCTD7 protein defects lead to epilepsy and cognitive dysfunction. We characterized Kctd7 expression patterns in the mouse brain during development and show that it is selectively enriched in specific regions as the brain matures. We further demonstrate that Kctd7-deficient mice develop seizures and locomotor defects with features similar to those observed in human KCTD7-associated diseases. We also show that Kctd7 is required for Purkinje cell survival in the cerebellum and that selective degeneration of these neurons is accompanied by defects in cerebellar microvascular organization and patterning. Taken together, these results define a new model for KCTD7-associated epilepsy and identify Kctd7 as a modulator of neuron survival and excitability linked to microvascular alterations in vulnerable regions.
    MeSH term(s) Animals ; Child ; Humans ; Mice ; Myoclonic Epilepsies, Progressive/genetics ; Phenotype ; Potassium Channels/genetics ; Purkinje Cells ; Seizures/genetics
    Chemical Substances KCTD7 protein, human ; KCTD7 protein, mouse ; Potassium Channels
    Language English
    Publishing date 2022-09-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.049642
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Neuronal signal-regulatory protein alpha drives microglial phagocytosis by limiting microglial interaction with CD47 in the retina.

    Jiang, Danye / Burger, Courtney A / Akhanov, Viktor / Liang, Justine H / Mackin, Robert D / Albrecht, Nicholas E / Andrade, Pilar / Schafer, Dorothy P / Samuel, Melanie A

    Immunity

    2022  Volume 55, Issue 12, Page(s) 2318–2335.e7

    Abstract: Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals that control this phagocytic clockwork remain largely undefined. Here, we show that ... ...

    Abstract Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals that control this phagocytic clockwork remain largely undefined. Here, we show that neuronal signal-regulatory protein alpha (SIRPα) is a permissive cue for microglial phagocytosis in the developing murine retina. Removal of neuronal, but not microglial, SIRPα reduced microglial phagocytosis, increased synpase numbers, and impaired circuit function. Conversely, prolonging neuronal SIRPα expression extended developmental microglial phagocytosis. These outcomes depended on the interaction of presynaptic SIRPα with postsynaptic CD47. Global CD47 deficiency modestly increased microglial phagocytosis, while CD47 overexpression reduced it. This effect was rescued by coexpression of neuronal SIRPα or codeletion of neuronal SIRPα and CD47. These data indicate that neuronal SIRPα regulates microglial phagocytosis by limiting microglial SIRPα access to neuronal CD47. This discovery may aid our understanding of synapse loss in neurological diseases.
    MeSH term(s) Mice ; Animals ; CD47 Antigen/metabolism ; Receptors, Immunologic/metabolism ; Macrophages/metabolism ; Phagocytosis/physiology ; Retina ; Antigens, Differentiation/metabolism
    Chemical Substances CD47 Antigen ; Receptors, Immunologic ; Antigens, Differentiation
    Language English
    Publishing date 2022-11-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2022.10.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4227: Show issues Location:
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  6. Article ; Online: Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.

    Amano, Hisayuki / Chaudhury, Arindam / Rodriguez-Aguayo, Cristian / Lu, Lan / Akhanov, Viktor / Catic, Andre / Popov, Yury V / Verdin, Eric / Johnson, Hannah / Stossi, Fabio / Sinclair, David A / Nakamaru-Ogiso, Eiko / Lopez-Berestein, Gabriel / Chang, Jeffrey T / Neilson, Joel R / Meeker, Alan / Finegold, Milton / Baur, Joseph A / Sahin, Ergun

    Cell metabolism

    2019  Volume 29, Issue 6, Page(s) 1274–1290.e9

    Abstract: Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent ... ...

    Abstract Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.
    MeSH term(s) Animals ; Cells, Cultured ; Down-Regulation/drug effects ; Down-Regulation/genetics ; Embryo, Mammalian ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; HEK293 Cells ; Humans ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/genetics ; Liver Cirrhosis/pathology ; Liver Cirrhosis/prevention & control ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Liver/drug effects ; Mitochondria, Liver/metabolism ; Nicotinamide Mononucleotide/pharmacology ; Sirtuin 1/genetics ; Sirtuin 1/metabolism ; Sirtuins/genetics ; Sirtuins/metabolism ; Telomerase/genetics ; Telomerase/metabolism ; Telomere Homeostasis/drug effects ; Telomere Homeostasis/physiology ; Telomere Shortening/drug effects ; Telomere Shortening/genetics ; Telomere Shortening/physiology
    Chemical Substances Nicotinamide Mononucleotide (1094-61-7) ; Telomerase (EC 2.7.7.49) ; Tert protein, mouse (EC 2.7.7.49) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-)
    Language English
    Publishing date 2019-03-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2176834-1
    ISSN 1932-7420 ; 1550-4131
    ISSN (online) 1932-7420
    ISSN 1550-4131
    DOI 10.1016/j.cmet.2019.03.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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