Wnt Signaling Promotes Neuronal Differentiation from Mesenchymal Stem Cells Through Activation of Tlx3§

Authors

  • Takako Kondo,

    1. Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Akihiro J. Matsuoka,

    1. Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Atsushi Shimomura,

    1. Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Karl R. Koehler,

    1. Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Rebecca J. Chan,

    1. Department of Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Josef M. Miller,

    1. Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA
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  • Edward F. Srour,

    1. Department of Pediatrics University of Michigan Medical School, Ann Arbor, Michigan, USA
    2. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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  • Eri Hashino

    Corresponding author
    1. Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA
    • Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut Street, R2-419, Indianapolis, Indiana 46202, USA

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    • Telephone: 317-278-9621; Fax: 317-278-9620


  • Author contributions: T.K.: conception and design, collection and/or assembly of data; data analysis and interpretation, manuscript writing; A.J.M.: conception and design, collection and/or assembly of data, data analysis and interpretation; A.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; K.R.K.: collection and/or assembly of data, data analysis and interpretation; R.J.C.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; J.M.M.: data analysis and interpretation, final approval of manuscript; E.F.S.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; E.H.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • First published online in STEM CELLS EXPRESS March 3, 2011.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

Abstract

Wnt/β-catenin signaling promotes neural differentiation by activation of the neuron-specific transcription factors, Neurogenin1 (Ngn1), NeuroD, and Brn3a, in the nervous system. As neurons in cranial sensory ganglia and dorsal root ganglia transiently express Ngn1, NeuroD, and Brn3a during embryonic development, we hypothesized that Wnt proteins could instructively promote a sensory neuronal fate from mesenchymal stem cells (MSCs) directed to differentiate into neurons. Consistent with our hypothesis, Wnt1 induced expression of sensory neuron markers including Ngn1, NeuroD, and Brn3a, as well as glutamatergic markers in neurally induced MSCs in vitro and promoted engraftment of transplanted MSCs in the inner ear bearing selective loss of sensory neurons in vivo. Given the consensus function of T-cell leukemia 3 (Tlx3), as a glutamatergic selector gene, we postulated that the effects of canonical Wnt signaling on sensory neuron and glutamatergic marker gene expression in MSCs may be mediated by Tlx3. We first confirmed that Wnt1 indeed upregulates Tlx3 expression, which can be suppressed by canonical Wnt inhibitors. Next, our chromatin immunoprecipitation assays revealed that T-cell factor 3/4, Wnt-activated DNA binding proteins, interact with a regulatory region of Tlx3 in MSCs after neural induction. Furthermore, we demonstrated that forced expression of Tlx3 in MSCs induced sensory and glutamatergic neuron markers after neural induction. Together, these results identify Tlx3 as a novel target for canonical Wnt signaling that confers somatic stem cells with a sensory neuron phenotype upon neural induction. STEM CELLS 2011;29:836–846

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