Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination
Stephen P.J. Fancy,Emily P. Harrington,Tracy J. Yuen,John C. Silbereis,Chao Zhao,Sergio E. Baranzini,Charlotte C. Bruce,Jose Otero,Eric J. Huang,Roel Nusse,Robin J.M. Franklin,David H. Rowitch +11 more
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TLDR
It is found that Axin2 function was essential for normal kinetics of remyelination and that it might serve as a pharmacological checkpoint in this process.Abstract:
Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.read more
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M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination
Veronique E. Miron,Amanda Boyd,Jing-Wei Zhao,Tracy J. Yuen,Tracy J. Yuen,Julia M. Ruckh,Jennifer L. Shadrach,Peter van Wijngaarden,Amy J. Wagers,Anna Williams,Robin J.M. Franklin,Charles ffrench-Constant +11 more
TL;DR: It is found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started and activin-A is identified as a therapeutic target for CNS regeneration.
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Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.
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TL;DR: Upon screening 1,000 bioactive molecules, this work identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination and demonstrates a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.
References
More filters
Journal ArticleDOI
Functional interaction of beta-catenin with the transcription factor LEF-1.
Jürgen Behrens,von Kries Jp,Michael Kühl,Bruhn L,Bruhn L,Doris Wedlich,Rudolf Grosschedl,Rudolf Grosschedl,Walter Birchmeier +8 more
TL;DR: β-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals from cell-adhesion components or wnt protein to the nucleus.
Journal ArticleDOI
XTcf-3 Transcription Factor Mediates β-Catenin-Induced Axis Formation in Xenopus Embryos
Miranda Molenaar,Marc van de Wetering,Mariëtte A. Oosterwegel,Josi Peterson-Maduro,Susan Godsave,Vladimir Korinek,Jeroen P. Roose,Olivier Destrée,Hans Clevers +8 more
TL;DR: It is proposed that signaling by beta-catenin involves complex formation with XT cf-3, followed by nuclear translocation and activation of specific XTcf-3 target genes, which suppresses endogenous axis specification upon injection into the dorsal blastomeres of a 4-cell-stage embryo.
Journal ArticleDOI
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
Shih Min A Huang,Yuji Mishina,Shanming Liu,Atwood K. Cheung,Frank Stegmeier,Gregory A. Michaud,Olga Charlat,Elizabeth Wiellette,Yue Zhang,Stephanie Wiessner,Marc Hild,Xiaoying Shi,Christine D. Wilson,Craig Mickanin,Vic E. Myer,Aleem Fazal,Ronald Tomlinson,Fabrizio C. Serluca,Wenlin Shao,Hong Cheng,Michael Shultz,Christina Rau,Markus Schirle,Judith Schlegl,Sonja Ghidelli,Stephen Fawell,Chris Lu,Daniel Curtis,Marc W. Kirschner,Christoph Lengauer,Peter Finan,John A. Tallarico,Tewis Bouwmeester,Jeffery A. Porter,Andreas Bauer,Feng Cong +35 more
TL;DR: This study uses a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription and reveals new mechanistic insights into the regulation of axin protein homeostasis, which presents new avenues for targeted Wnt pathway therapies.
Journal ArticleDOI
Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis
Christopher Lock,Guy Hermans,Rosetta Pedotti,Andrea Brendolan,Eric E. Schadt,Hideki Garren,Annette Langer-Gould,Samuel Strober,Barbara Cannella,John Allard,Klonowski Paul,Angela Austin,Nagin Lad,Naftali Kaminski,Stephen J. Galli,Jorge R. Oksenberg,Cedric S. Raine,Renu A. Heller,Lawrence Steinman +18 more
TL;DR: Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy, and results in EAE corroborate the microarray studies on MS lesions.
Journal ArticleDOI
Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway
TL;DR: The results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors, and participates in a negative feedback loop which could serve to limit the duration or intensity of a Wnt-initiated signal.