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  1. Article ; Online: RAS and beyond

    Corina Anastasaki / Paola Orozco / David H. Gutmann

    Disease Models & Mechanisms, Vol 15, Iss

    the many faces of the neurofibromatosis type 1 protein

    2022  Volume 2

    Abstract: Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the ... ...

    Abstract Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.
    Keywords neurofibromin ; ras ; cyclic amp ; tumor suppressor ; Medicine ; R ; Pathology ; RB1-214
    Subject code 610
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Generation of human induced pluripotent stem cell-derived cerebral organoids for cellular and molecular characterization

    Corina Anastasaki / Anna F. Wilson / Alexander S. Chen / Michelle L. Wegscheid / David H. Gutmann

    STAR Protocols, Vol 3, Iss 1, Pp 101173- (2022)

    2022  

    Abstract: Summary: Human induced pluripotent stem cell (hiPSC)-derived cerebral organoids (COs) can serve as an in vitro model for studying normal and pathologic human brain development. Here, we optimized existing protocols to streamline the generation of ... ...

    Abstract Summary: Human induced pluripotent stem cell (hiPSC)-derived cerebral organoids (COs) can serve as an in vitro model for studying normal and pathologic human brain development. Here, we optimized existing protocols to streamline the generation of forebrain COs from hiPSCs. We employ these COs to define the impact of disease-causing mutations on cell fate, differentiation, maturation, and morphology relevant to neurodevelopmental disorders. Although limited to forebrain CO identity, this schema requires minimal external interference and is amenable to low-throughput biochemical assays.For complete details on the use and execution of this profile, please refer to Anastasaki et al. (2020) and Wegscheid et al. (2021).
    Keywords Cell Biology ; Cell culture ; Developmental biology ; Health Sciences ; Neuroscience ; Stem Cells ; Science (General) ; Q1-390
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Neurofibromin 1 mutations impair the function of human induced pluripotent stem cell-derived microglia

    Leonard D. Kuhrt / Edyta Motta / Nirmeen Elmadany / Hannah Weidling / Raphaela Fritsche-Guenther / Ibrahim E. Efe / Olivia Cobb / Jit Chatterjee / Lucy G. Boggs / Marina Schnauß / Sebastian Diecke / Marcus Semtner / Corina Anastasaki / David H. Gutmann / Helmut Kettenmann

    Disease Models & Mechanisms, Vol 16, Iss

    2023  Volume 12

    Keywords microglia ; neurofibromatosis 1 ; human induced pluripotent stem cells ; purinergic receptors ; phagocytosis ; motility ; Medicine ; R ; Pathology ; RB1-214
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1

    Corina Anastasaki / Juan Mo / Ji-Kang Chen / Jit Chatterjee / Yuan Pan / Suzanne M. Scheaffer / Olivia Cobb / Michelle Monje / Lu Q. Le / David H. Gutmann

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 17

    Abstract: Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that Nf1 mutations differentially drive both central and peripheral nervous system tumor growth in mice through ... ...

    Abstract Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that Nf1 mutations differentially drive both central and peripheral nervous system tumor growth in mice through reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function.
    Keywords Science ; Q
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

    Xiaofan Guo / Yuan Pan / Min Xiong / Shilpa Sanapala / Corina Anastasaki / Olivia Cobb / Sonika Dahiya / David H. Gutmann

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas. ...

    Abstract The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

    Xiaofan Guo / Yuan Pan / Min Xiong / Shilpa Sanapala / Corina Anastasaki / Olivia Cobb / Sonika Dahiya / David H. Gutmann

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas. ...

    Abstract The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.
    Keywords Science ; Q
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish

    Corina Anastasaki / Katherine A. Rauen / E. Elizabeth Patton

    Disease Models & Mechanisms, Vol 5, Iss 4, Pp 546-

    2012  Volume 552

    Abstract: SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have ...

    Abstract SUMMARY Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAFQ257R kinase-active allele and the BRAFG596V kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAFCFC mutations.
    Keywords Medicine ; R ; Pathology ; RB1-214
    Subject code 616
    Language English
    Publishing date 2012-07-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

    Kairong Li / Ashley N. Turner / Min Chen / Stephanie N. Brosius / Trenton R. Schoeb / Ludwine M. Messiaen / David M. Bedwell / Kurt R. Zinn / Corina Anastasaki / David H. Gutmann / Bruce R. Korf / Robert A. Kesterson

    Disease Models & Mechanisms, Vol 9, Iss 7, Pp 759-

    2016  Volume 767

    Abstract: Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing ... ...

    Abstract Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.
    Keywords Neurofibromatosis type 1 ; Patient-derived mouse models ; Nonsense mutation ; Missense mutation ; Medicine ; R ; Pathology ; RB1-214
    Subject code 616
    Language English
    Publishing date 2016-07-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: The INT6 cancer gene and MEK signaling pathways converge during zebrafish development.

    Michal Grzmil / Danny Whiting / John Maule / Corina Anastasaki / James F Amatruda / Robert N Kelsh / Chris J Norbury / E Elizabeth Patton

    PLoS ONE, Vol 2, Iss 9, p e

    2007  Volume 959

    Abstract: Int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (MMTV) insertions. INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an ... ...

    Abstract Int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (MMTV) insertions. INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an animal model to study Int-6 physiological function has been lacking.Here, we create an in vivo model of Int6 function in zebrafish, and through genetic and chemical-genetic approaches implicate Int6 as a tissue-specific modulator of MEK-ERK signaling. We find that Int6 is required for normal expression of MEK1 protein in human cells, and for Erk signaling in zebrafish embryos. Loss of either Int6 or Mek signaling causes defects in craniofacial development, and Int6 and Erk-signaling have overlapping domains of tissue expression.Our results provide new insight into the physiological role of vertebrate Int6, and have implications for the treatment of human tumors displaying altered INT6 expression.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2007-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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