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  1. Article: Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice.

    Dakubo, Gabriel D / Mazerolle, Chantal J / Wallace, Valerie A

    Journal of neuro-oncology

    2006  Volume 79, Issue 3, Page(s) 221–227

    Abstract: Hedgehog (Hh), Notch, and Wingless (Wnt) signaling control normal development of the cerebellum, and dysregulation of these signaling pathways are associated with medulloblastoma (MB). As an initial step in the study of the role of interacting signaling ... ...

    Abstract Hedgehog (Hh), Notch, and Wingless (Wnt) signaling control normal development of the cerebellum, and dysregulation of these signaling pathways are associated with medulloblastoma (MB). As an initial step in the study of the role of interacting signaling pathways in MB pathogenesis, we demonstrate the expression of several components of the Notch and Wnt signaling pathways, and activation of Notch signaling in MB from Ptch +/- mice that have elevated Hh signaling. We also show a marked downregulation in the expression of Notch2, Jagged1, Hes1, mSfrp1, and mFrz7 in cerebella of developing mice with reduced Hh signaling, suggesting that Hh signaling regulates the expression of these genes. Together with recent published data, these findings indicate that Hh signaling might synergize simultaneously with Notch and Wnt signaling in MB development by controlling Notch and Wnt pathway ligand, receptor and/or target gene expression.
    MeSH term(s) Animals ; Carrier Proteins/metabolism ; Cell Transformation, Neoplastic/metabolism ; Cerebellar Neoplasms/metabolism ; Heterozygote ; Immunohistochemistry ; In Situ Hybridization ; Medulloblastoma/metabolism ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Patched Receptors ; Patched-1 Receptor ; RNA, Messenger/analysis ; Receptors, Cell Surface/genetics ; Receptors, Notch/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology ; Wnt Proteins/metabolism
    Chemical Substances Carrier Proteins ; Hhip protein, mouse ; Membrane Glycoproteins ; Patched Receptors ; Patched-1 Receptor ; Ptch1 protein, mouse ; RNA, Messenger ; Receptors, Cell Surface ; Receptors, Notch ; Wnt Proteins
    Language English
    Publishing date 2006-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604875-4
    ISSN 1573-7373 ; 0167-594X
    ISSN (online) 1573-7373
    ISSN 0167-594X
    DOI 10.1007/s11060-006-9132-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Control of glial precursor cell development in the mouse optic nerve by sonic hedgehog from retinal ganglion cells.

    Dakubo, Gabriel D / Beug, Shawn T / Mazerolle, Chantal J / Thurig, Sherry / Wang, Yaping / Wallace, Valerie A

    Brain research

    2008  Volume 1228, Page(s) 27–42

    Abstract: The development of glial precursor cells in the mammalian optic nerve depends on retinal ganglion cell (RGC) axons, but the signals that mediate this neuron-to-glia interaction have not been fully characterized. Sonic hedgehog (Shh) is expressed by RGCs, ...

    Abstract The development of glial precursor cells in the mammalian optic nerve depends on retinal ganglion cell (RGC) axons, but the signals that mediate this neuron-to-glia interaction have not been fully characterized. Sonic hedgehog (Shh) is expressed by RGCs, and we showed previously that it is required for the specification of astrocyte lineage cells at the optic disc. To study the role of RGC-derived Shh on astrocyte development at later developmental stages, we generated mice with a conditional ablation of Shh in the peripheral retina and analyzed gene expression and glial cell development in the optic nerve. Astrocyte development was initiated in the optic nerves of these mutant mice; however, the expression of Hedgehog (Hh) target genes, Gli1 and Ptch1 and cell cycle genes, Ccnd1 and Cdc25b in the optic nerves were downregulated. Astrocyte proliferation was markedly reduced. Oligodendrocyte precursor cells were fewer in the optic nerves of mutant mice, possibly as a consequence of reduced secretion of growth factors by astrocytes. At a later developmental stage, optic nerve axons displayed signs of Wallerian degeneration, including reduction of astrocyte processes, degenerating glial cells and formation of distended axons. We also demonstrate that the Hh pathway can be activated in optic nerve-derived astrocytes in vitro, but fails to induce cell cycle gene expression and proliferation. RGC-derived Shh signalling isthus necessary in vivo for maintenance of astrocyte proliferation, affecting both axo-glial and normal glial cell development in the optic nerve.
    MeSH term(s) Animals ; Astrocytes/cytology ; Astrocytes/metabolism ; Blotting, Western ; Cell Cycle/genetics ; Cell Cycle/physiology ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Proliferation ; Cells, Cultured ; Cyclin D ; Cyclins/genetics ; Cyclins/metabolism ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Hedgehog Proteins/physiology ; Immunohistochemistry ; In Situ Hybridization ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Electron, Transmission ; Neuroglia/cytology ; Neuroglia/metabolism ; Oligodendroglia/cytology ; Oligodendroglia/metabolism ; Optic Nerve/growth & development ; Optic Nerve/metabolism ; Optic Nerve/ultrastructure ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism ; Retinal Ganglion Cells/cytology ; Retinal Ganglion Cells/metabolism ; Retinal Ganglion Cells/ultrastructure ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics ; Signal Transduction/physiology ; Zinc Finger Protein GLI1 ; cdc25 Phosphatases/genetics ; cdc25 Phosphatases/metabolism
    Chemical Substances Cyclin D ; Cyclins ; Gli protein, mouse ; Hedgehog Proteins ; Kruppel-Like Transcription Factors ; Patched Receptors ; Patched-1 Receptor ; Ptch1 protein, mouse ; Receptors, Cell Surface ; Shh protein, mouse ; Zinc Finger Protein GLI1 ; Cdc25b protein, mouse (EC 3.1.3.48) ; cdc25 Phosphatases (EC 3.1.3.48)
    Language English
    Publishing date 2008-09-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2008.06.058
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina.

    Wang, Yaping / Dakubo, Gabriel D / Thurig, Sherry / Mazerolle, Chantal J / Wallace, Valerie A

    Development (Cambridge, England)

    2005  Volume 132, Issue 22, Page(s) 5103–5113

    Abstract: The timing of cell cycle exit and temporal changes in the developmental competence of precursor cells are key components for the establishment of the normal complement of cell types in the mammalian retina. The identity of cell extrinsic cues that ... ...

    Abstract The timing of cell cycle exit and temporal changes in the developmental competence of precursor cells are key components for the establishment of the normal complement of cell types in the mammalian retina. The identity of cell extrinsic cues that control these processes is largely unknown. We showed previously in mouse retina that sonic hedgehog (Shh) signalling from retinal ganglion cells (RGCs) to retinal precursor cells (RPC) is required for the establishment of normal retinal organization. Here, we show that conditional ablation of Shh expression in the peripheral mouse results in a depletion of the RPC pool, owing to precocious cell-cycle exit and neuronal differentiation. These changes were correlated with the downregulation of cyclin D1 and Hes1 gene expression. Shh inactivation also results in an increase in RGC number owing to a bias of RPC towards RGC production. In contrast to zebrafish, where Shh signalling drives cell cycle exit and RGC development, our findings indicate that in the mouse retina Shh signalling is required to maintain RPC proliferation and to control the timing of RGC development.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/biosynthesis ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Cell Cycle/physiology ; Cell Differentiation/physiology ; Cell Proliferation ; Down-Regulation ; Hedgehog Proteins ; Homeodomain Proteins/biosynthesis ; Homeodomain Proteins/genetics ; Integrases/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Retina/embryology ; Retinal Ganglion Cells/cytology ; Retinal Ganglion Cells/physiology ; Signal Transduction/physiology ; Trans-Activators/physiology ; Transcription Factor HES-1
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Hedgehog Proteins ; Hes1 protein, mouse ; Homeodomain Proteins ; Shh protein, mouse ; Trans-Activators ; Transcription Factor HES-1 ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
    Language English
    Publishing date 2005-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.02096
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Characterization of transgene expression and Cre recombinase activity in a panel of Thy-1 promoter-Cre transgenic mice.

    Campsall, Katrina D / Mazerolle, Chantal J / De Repentingy, Yves / Kothary, Rashmi / Wallace, Valerie A

    Developmental dynamics : an official publication of the American Association of Anatomists

    2002  Volume 224, Issue 2, Page(s) 135–143

    Abstract: The regulatory elements of the murine Thy1.2 gene were used to drive Cre recombinase expression in the nervous system (NS) of transgenic mice. Eleven Thy1-Cre lines exhibited transgene expression in several regions of the central and peripheral nervous ... ...

    Abstract The regulatory elements of the murine Thy1.2 gene were used to drive Cre recombinase expression in the nervous system (NS) of transgenic mice. Eleven Thy1-Cre lines exhibited transgene expression in several regions of the central and peripheral nervous systems, including the cerebral cortex, cerebellum, spinal cord, retina, and dorsal root ganglion. Thy1-Cre expression also resulted in region-specific activation of Cre reporter transgenes. Although Thy-1 expression is normally initiated in postmitotic neurons in the perinatal period, we show that the Thy-1.2 expression cassette drives Cre expression in immature proliferative zones in the NS as early as embryonic day 11 and in non-neural tissue. The Thy1.2 transgene cassette, therefore, does not impart transgene expression that is restricted to the NS or to postmitotic neurons within the NS. This panel of Thy1-Cre transgenic mice, however, will be useful reagents for the ablation of genes whose transcripts are spatially or temporally restricted in the developing NS.
    MeSH term(s) Animals ; Blotting, Southern ; Cell Nucleus/metabolism ; Central Nervous System/embryology ; DNA, Complementary/metabolism ; Gene Expression Regulation, Developmental ; Genes, Reporter ; In Situ Hybridization ; Integrases/genetics ; Integrases/physiology ; Isoantibodies/genetics ; Isoantibodies/physiology ; Mice ; Mice, Transgenic ; Mitosis ; Models, Genetic ; Promoter Regions, Genetic ; Retina/embryology ; Time Factors ; Transgenes ; Viral Proteins/genetics ; Viral Proteins/physiology
    Chemical Substances DNA, Complementary ; Isoantibodies ; Viral Proteins ; anti-Thy antibody ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
    Language English
    Publishing date 2002-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.10092
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  5. Article: Direct and indirect effects of hedgehog pathway activation in the mammalian retina.

    Yu, Chuan / Mazerolle, Chantal J / Thurig, Sherry / Wang, Yaping / Pacal, Marek / Bremner, Rod / Wallace, Valerie A

    Molecular and cellular neurosciences

    2006  Volume 32, Issue 3, Page(s) 274–282

    Abstract: The morphogen Sonic hedgehog (Shh) is expressed by the projection neurons of the retina, retinal ganglion cells (RGCs) and promotes retinal precursor cell (RPC) proliferation. To distinguish between direct and indirect effects of Hedgehog (Hh) pathway ... ...

    Abstract The morphogen Sonic hedgehog (Shh) is expressed by the projection neurons of the retina, retinal ganglion cells (RGCs) and promotes retinal precursor cell (RPC) proliferation. To distinguish between direct and indirect effects of Hedgehog (Hh) pathway activation in the perinatal mouse retina, we followed the fate of cells that expressed a constitutively active allele of Smoothened (SMO-M2), the signal transduction component of the Hh pathway. SMO-M2 expression promoted a cell-autonomous increase in CyclinD1 expression and RPC proliferation and promoted the development of cells with an inner nuclear layer identity. SMO-M2 expression also inhibited rhodopsin expression in uninfected cells, thus highlighting an unexpected non-cell autonomous effect of Hh pathway activation on photoreceptor development.
    MeSH term(s) Animals ; Cells, Cultured ; Hedgehog Proteins ; Humans ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; NIH 3T3 Cells ; Receptors, G-Protein-Coupled/biosynthesis ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/physiology ; Retina/growth & development ; Retina/metabolism ; Retina/physiology ; Signal Transduction/physiology ; Smoothened Receptor ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Trans-Activators/physiology
    Chemical Substances Hedgehog Proteins ; Receptors, G-Protein-Coupled ; SHH protein, human ; Smo protein, mouse ; Smoothened Receptor ; Trans-Activators
    Language English
    Publishing date 2006-07
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1046640-x
    ISSN 1095-9327 ; 1044-7431
    ISSN (online) 1095-9327
    ISSN 1044-7431
    DOI 10.1016/j.mcn.2006.05.002
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  6. Article: Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development.

    Black, Graeme C M / Mazerolle, Chantal J / Wang, Yaping / Campsall, Katrina D / Petrin, Dino / Leonard, Brian C / Damji, Karim F / Evans, D Gareth / McLeod, David / Wallace, Valerie A

    Human molecular genetics

    2003  Volume 12, Issue 24, Page(s) 3269–3276

    Abstract: Mutations in Patched (PTCH), encoding the Hedgehog (Hh) receptor, underlie Basal Cell Naevus syndrome (BCNS) and, in addition to tumor predisposition, are associated with a wide range of 'patterning' defects. The basis for the underlying patterning ... ...

    Abstract Mutations in Patched (PTCH), encoding the Hedgehog (Hh) receptor, underlie Basal Cell Naevus syndrome (BCNS) and, in addition to tumor predisposition, are associated with a wide range of 'patterning' defects. The basis for the underlying patterning problems in Hh-dependent tissues in BCNS and their long-term consequences on tissue homeostasis are, however, not known. Hh signaling is required for normal growth and organization of the mammalian retina and we show that PtchlacZ+/- mice exhibit vitreoretinal abnormalities resembling those found in BCNS patients. The retinas of PtchlacZ+/- mice exhibit abnormal cell cycle regulation, which culminates in photoreceptor dysplasia and Müller cell-derived gliosis. In BCNS, the intraretinal glial response results in epiretinal membrane (ERM) formation, a proliferative and contractile response on the retinal surface. ERMs are a cause of significant visual loss in the general, especially elderly, population. We hypothesize that alteration of Müller cell Hh signaling may play a role in the pathogenesis of such age-related 'idiopathic' ERMs.
    MeSH term(s) Animals ; Basal Cell Nevus Syndrome/genetics ; Basal Cell Nevus Syndrome/metabolism ; Basal Cell Nevus Syndrome/pathology ; Gene Expression Regulation ; Hedgehog Proteins ; Humans ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Transgenic ; Mutation ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface ; Retina/abnormalities ; Retina/growth & development ; Retina/ultrastructure ; Retinal Dysplasia/genetics ; Retinal Dysplasia/pathology ; Signal Transduction ; Trans-Activators/genetics ; Trans-Activators/metabolism
    Chemical Substances Hedgehog Proteins ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; PTCH1 protein, human ; Patched Receptors ; Patched-1 Receptor ; Ptch1 protein, mouse ; Receptors, Cell Surface ; Trans-Activators
    Language English
    Publishing date 2003-10-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddg356
    Database MEDical Literature Analysis and Retrieval System OnLINE

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