Wnt signaling promotes neuronal differentiation from mesenchymal stem cells through activation of Tlx3

Takako Kondo, Akihiro J. Matsuoka, Atsushi Shimomura, Karl R. Koehler, Rebecca Chan, Josef M. Miller, Edward Srour, Eri Hashino

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Wnt/β-catenin signaling promotes neural differentiation by activation of the neuron-specific transcription factors, Neurogeninl (Ngnl), NeuroD, and Brn3a, in the nervous system. As neurons in cranial sensory ganglia and dorsal root ganglia transiently express Ngnl, 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 Ngnl, 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 (77x3), as a glu tamatergic 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.

Original languageEnglish
Pages (from-to)836-846
Number of pages11
JournalStem Cells
Volume29
Issue number5
DOIs
StatePublished - May 2011

Fingerprint

Sensory Receptor Cells
Mesenchymal Stromal Cells
Transcription Factor 7-Like 1 Protein
Neurons
Transcription Factor 7-Like 2 Protein
Wnt Proteins
Sensory Ganglia
T-Cell Leukemia
Catenins
Adult Stem Cells
Chromatin Immunoprecipitation
Nucleic Acid Regulatory Sequences
DNA-Binding Proteins
Spinal Ganglia
Inner Ear
Nervous System
Embryonic Development
Transcription Factors
Up-Regulation
Phenotype

Keywords

  • Differentiation
  • Glutamatergic neurons
  • Mesenchymal stem cells
  • Tlx3
  • Transplantation
  • Wnt

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Wnt signaling promotes neuronal differentiation from mesenchymal stem cells through activation of Tlx3. / Kondo, Takako; Matsuoka, Akihiro J.; Shimomura, Atsushi; Koehler, Karl R.; Chan, Rebecca; Miller, Josef M.; Srour, Edward; Hashino, Eri.

In: Stem Cells, Vol. 29, No. 5, 05.2011, p. 836-846.

Research output: Contribution to journalArticle

Kondo, Takako ; Matsuoka, Akihiro J. ; Shimomura, Atsushi ; Koehler, Karl R. ; Chan, Rebecca ; Miller, Josef M. ; Srour, Edward ; Hashino, Eri. / Wnt signaling promotes neuronal differentiation from mesenchymal stem cells through activation of Tlx3. In: Stem Cells. 2011 ; Vol. 29, No. 5. pp. 836-846.
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