Wnt Signaling Promotes Neuronal Differentiation from Mesenchymal Stem Cells Through Activation of Tlx3
Tóm tắt
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.
Từ khóa
Tài liệu tham khảo
Jori, 2005, Molecular pathways involved in neural in vitro differentiation of marrow stromal stem cells, J Cell Biochem, 94, 645, 10.1002/jcb.20315
Schwartz, 2002, Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells, J Clin Invest, 109, 1291, 10.1172/JCI0215182
Bae, 2007, Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration, Stem Cells, 25, 1307, 10.1634/stemcells.2006-0561
Dezawa, 2004, Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation, J Clin Invest, 113, 1701, 10.1172/JCI200420935
Ohtaki, 2008, Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses, Proc Natl Acad Sci USA, 105, 14638, 10.1073/pnas.0803670105
Neuhuber, 2005, Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations, Brain Res, 1035, 73, 10.1016/j.brainres.2004.11.055
Yu, 2008, TSP-1 secreted by bone marrow stromal cells contributes to retinal ganglion cell neurite outgrowth and survival, Plos One, 3, e2470, 10.1371/journal.pone.0002470
Huang, 2001, Brn3a is a transcriptional regulator of soma size, target field innervation and axon pathfinding of inner ear sensory neurons, Development, 128, 2421, 10.1242/dev.128.13.2421
Lanier, 2007, Brn3a target gene recognition in embryonic sensory neurons, Dev Biol, 302, 703, 10.1016/j.ydbio.2006.10.050
Ma, 2003, Brn3a regulation of TrkA/NGF receptor expression in developing sensory neurons, Development, 130, 3525, 10.1242/dev.00582
Kondo, 2005, Sonic hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells, Proc Natl Acad Sci USA, 102, 4789, 10.1073/pnas.0408239102
Logan, 2004, The Wnt signaling pathway in development and disease, Annu Rev Cell Dev Biol, 20, 781, 10.1146/annurev.cellbio.20.010403.113126
Grigoryan, 2008, Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice, Genes Dev, 22, 2308, 10.1101/gad.1686208
Toledo, 2008, Wnt signaling in neuroprotection and stem cell differentiation, Prog Neurobiol, 86, 281, 10.1016/j.pneurobio.2008.08.001
Hari, 2002, Lineage-specific requirements of beta-catenin in neural crest development, J Cell Biol, 159, 867, 10.1083/jcb.200209039
Lee, 2004, Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells, Science (New York, NY), 303, 1020, 10.1126/science.1091611
Ohyama, 2006, Wnt signals mediate a fate decision between otic placode and epidermis, Development, 133, 865, 10.1242/dev.02271
Freter, 2008, Progressive restriction of otic fate: the role of FGF and Wnt in resolving inner ear potential, Development, 135, 3415, 10.1242/dev.026674
Salero, 2007, Differentiation of ES cells into cerebellar neurons, Proc Natl Acad Sci USA, 104, 2997, 10.1073/pnas.0610879104
Otero, 2004, Beta-catenin signaling is required for neural differentiation of embryonic stem cells, Development, 131, 3545, 10.1242/dev.01218
Kuwabara, 2009, Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis, Nat Neurosci, 12, 1097, 10.1038/nn.2360
Chitteti, 2010, Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function, Blood, 115, 3239, 10.1182/blood-2009-09-246173
Shtutman, 1999, The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway, Proc Natl Acad Sci USA, 96, 5522, 10.1073/pnas.96.10.5522
Matsuoka, 2006, In vivo and in vitro characterization of bone marrow-derived stem cells in the cochlea, Laryngoscope, 116, 1363, 10.1097/01.mlg.0000225986.18790.75
Matsuoka, 2007, Enhanced survival of bone-marrow-derived pluripotent stem cells in an animal model of auditory neuropathy, Laryngoscope, 117, 1629, 10.1097/MLG.0b013e31806bf282
Ling, 2009, Wnt signaling controls the fate of mesenchymal stem cells, Gene, 433, 1, 10.1016/j.gene.2008.12.008
Pruszak, 2009, CD15, CD24, and CD29 define a surface biomarker code for neural lineage differentiation of stem cells, Stem Cells, 27, 2928, 10.1002/stem.211
Elghetany, 2002, Assessment of CD24 expression on bone marrow neutrophilic granulocytes: CD24 is a marker for the myelocytic stage of development, Am J Hematol, 71, 348, 10.1002/ajh.10176
Droin, 2010, Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia, Blood, 115, 78, 10.1182/blood-2009-05-224352
Cheng, 2004, Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates, Nat Neurosci, 7, 510, 10.1038/nn1221
Cheng, 2005, Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes, Nat Neurosci, 8, 1510, 10.1038/nn1569
Kondo, 2008, Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells, Proc Natl Acad Sci USA, 105, 5780, 10.1073/pnas.0708704105
Borghini, 2006, Nuclear factor Y drives basal transcription of the human TLX3, a gene overexpressed in T-cell acute lymphocytic leukemia, Mol Cancer Res, 4, 635, 10.1158/1541-7786.MCR-05-0250
Schmiedt, 2002, Effects of furosemide applied chronically to the round window: A model of metabolic presbyacusis, J Neurosci, 22, 9643, 10.1523/JNEUROSCI.22-21-09643.2002
Giordano, 2007, From the laboratory bench to the patient's bedside: An update on clinical trials with mesenchymal stem cells, J Cell Physiol, 211, 27, 10.1002/jcp.20959
Le Blanc, 2005, Mesenchymal stem cells: Progress toward promise, Cytotherapy, 7, 36, 10.1016/S1465-3249(05)70787-8
Liu, 2005, Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract, Nat Neurosci, 8, 1151, 10.1038/nn1520
Wolf, 2008, Phosphatidylinositol-3-kinase-atypical protein kinase C signaling is required for Wnt attraction and anterior-posterior axon guidance, J Neurosci, 28, 3456, 10.1523/JNEUROSCI.0029-08.2008
Fox, 2010, Membrane properties of neuron-like cells generated from adult human bone-marrow-derived mesenchymal stem cells, Stem Cells Dev, 19, 1831, 10.1089/scd.2010.0089
Cho, 2005, Neurons derived from human mesenchymal stem cells show synaptic transmission and can be induced to produce the neurotransmitter substance P by interleukin-1 alpha, Stem Cells, 23, 383, 10.1634/stemcells.2004-0251
Wislet-Gendebien, 2005, Plasticity of cultured mesenchymal stem cells: Switch from nestin-positive to excitable neuron-like phenotype, Stem Cells, 23, 392, 10.1634/stemcells.2004-0149
Asahara, 1999, Pbx-Hox heterodimers recruit coactivator-corepressor complexes in an isoform-specific manner, Mol Cell Biol, 19, 8219, 10.1128/MCB.19.12.8219
Moens, 2006, Hox cofactors in vertebrate development, Dev Biol, 291, 193, 10.1016/j.ydbio.2005.10.032
Chang, 1996, Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus, Mol Cell Biol, 16, 1734, 10.1128/MCB.16.4.1734
Peltenburg, 1997, Specific residues in the Pbx homeodomain differentially modulate the DNA-binding activity of Hox and engrailed proteins, Development, 124, 1089, 10.1242/dev.124.5.1089
Lawoko-Kerali, 2004, GATA3 and NeuroD distinguish auditory and vestibular neurons during development of the mammalian inner ear, Mech Dev, 121, 287, 10.1016/j.mod.2003.12.006
Liu, 2008, An essential role for Frizzled5 in neuronal survival in the parafascicular nucleus of the thalamus, J Neurosci, 28, 5641, 10.1523/JNEUROSCI.1056-08.2008
Seitz, 2010, Norrin mediates neuroprotective effects on retinal ganglion cells via activation of the Wnt/beta-catenin signaling pathway and the induction of neuroprotective growth factors in Muller cells, J Neurosci, 30, 5998, 10.1523/JNEUROSCI.0730-10.2010
Hayashi, 2009, A trophic role for Wnt-Ror kinase signaling during developmental pruning in Caenorhabditis elegans, Nat Neurosci, 12, 981, 10.1038/nn.2347
Davidson, 2007, Wnt3a regulates survival, expansion, and maintenance of neural progenitors derived from human embryonic stem cells, Mol Cell Neurosci, 36, 408, 10.1016/j.mcn.2007.07.013
Castelo-Branco, 2003, Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a, Proc Natl Acad Sci USA, 100, 12747, 10.1073/pnas.1534900100
Gogolla, 2009, Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus, Neuron, 62, 510, 10.1016/j.neuron.2009.04.022