Sox2
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The role of Sox2 in neurosensory development is not yet fully understood. Using mice with conditional Islet1-cre mediated deletion of Sox2, we explored the function of Sox2 in neurosensory development in a model with limited cell type diversification, the inner ear. In Sox2 conditional mutants, neurons initially appear to form normally, whereas late- differentiating neurons of the cochlear apex never form. Variable numbers of hair cells differentiate in the utricle, saccule, and cochlear base but sensory epithelium formation is completely absent in the apex and all three cristae of the semicircular canal ampullae. Hair cells differentiate only in sensory epithelia known or proposed to have a lineage relationship of neurons and hair cells. All initially formed neurons lacking hair cell targets die by apoptosis days after they project toward non-existing epithelia. Therefore, late neuronal development depends directly on Sox2 for differentiation and on the survival of hair cells, possibly derived from common neurosensory precursors.
- MeSH
- delece genu MeSH
- myši transgenní MeSH
- myši MeSH
- neurogeneze fyziologie MeSH
- sakulus a utrikulus cytologie embryologie MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- vláskové buňky cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
As cancer stem cells (CSCs) are resistant to chemotherapy, radiotherapy and targeted molecular therapy, immunotherapy of tumors could be aimed at their elimination. Markers specific for CSCs have not been identified to date, but microarray analyses have shown that CSCs and embryonic stem cells use similar transcriptional programs, thus suggesting the production of shared transcription factors. In this study, we developed an experimental DNA vaccine against the transcription factor Sox2 that is important for self-renewal of stem cells and is overexpressed in numerous human cancers. The Sox2 gene was codon optimized for the expression in human cells, its sequences encoding two nuclear localization signals (NLSs) were mutagenized, and the sequence coding for the PADRE helper epitope was fused with its 5' terminus. While codon optimization did not increase Sox2 production and mutagenesis in NLSs only partially reduced nuclear localization of Sox2, the addition of the PADRE epitope was crucial for the enhancement of Sox2 immunogenicity. The antitumor effect was shown after immunization against mouse oncogenic TC-1/B7 cells derived from the lung cancer cell line TC-1 and characterized by high Sox2 production. Sox2-specific reactivity in an ELISPOT assay was further augmented by the depletion of regulatory T (Treg) cells, but this depletion did not enhance the antitumor effect. These data demonstrated the induction of immune responses against the Sox2 self-antigen, but did not confirm the usefulness of Treg depletion when combined with antitumor vaccination.
- MeSH
- buněčné jádro metabolismus MeSH
- buňky NIH 3T3 MeSH
- DNA vakcíny farmakologie MeSH
- imunizace MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky metabolismus patologie MeSH
- nádory plic patologie MeSH
- regulační T-lymfocyty metabolismus MeSH
- transkripční faktory SOXB1 antagonisté a inhibitory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The three most frequent pediatric sarcomas, i.e., Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, were examined in this study: three cell lines derived from three primary tumor samples were analyzed from each of these tumor types. Detailed comparative analysis of the expression of three putative cancer stem cell markers related to sarcomas-ABCG2, CD133, and nestin-was performed on both primary tumor tissues and corresponding cell lines. The obtained results showed that the frequency of ABCG2-positive and CD133-positive cells was predominantly increased in the respective cell lines but that the high levels of nestin expression were reduced in both osteosarcomas and rhabdomyosarcomas under in vitro conditions. These findings suggest the selection advantage of cells expressing ABCG2 or CD133, but the functional tests in NOD/SCID gamma mice did not confirm the tumorigenic potential of cells harboring this phenotype. Subsequent analysis of the expression of common stem cell markers revealed an evident relationship between the expression of the transcription factor Sox2 and the tumorigenicity of the cell lines in immunodeficient mice: the Sox2 levels were highest in the two cell lines that were demonstrated as tumorigenic. Furthermore, Sox2-positive cells were found in the respective primary tumors and all xenograft tumors showed apparent accumulation of these cells. All of these findings support our conclusion that regardless of the expression of ABCG2, CD133 and nestin, only cells displaying increased Sox2 expression are directly involved in tumor initiation and growth; therefore, these cells fit the definition of the cancer stem cell phenotype.
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- antigen AC133 metabolismus MeSH
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- myši inbrední NOD MeSH
- myši SCID MeSH
- myši MeSH
- nádorová transformace buněk metabolismus patologie MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky metabolismus patologie MeSH
- nádorové proteiny metabolismus MeSH
- nestin metabolismus MeSH
- osteosarkom metabolismus patologie MeSH
- předškolní dítě MeSH
- rhabdomyosarkom metabolismus patologie MeSH
- sarkom metabolismus patologie MeSH
- transkripční faktory SOXB1 metabolismus MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
SOX2 is essential for maintaining neurosensory stem cell properties, although its involvement in the early neurosensory development of cranial placodes remains unclear. To address this, we used Foxg1-Cre to conditionally delete Sox2 during eye, ear, and olfactory placode development. Foxg1-Cre mediated early deletion of Sox2 eradicates all olfactory placode development, and disrupts retinal development and invagination of the lens placode. In contrast to the lens and olfactory placodes, the ear placode invaginates and delaminates NEUROD1 positive neurons. Furthermore, we show that SOX2 is not necessary for early ear neurogenesis, since the early inner ear ganglion is formed with near normal central projections to the hindbrain and peripheral projections to the undifferentiated sensory epithelia of E11.5-12.5 ears. However, later stages of ear neurosensory development, in particular, the late forming auditory system, critically depend on the presence of SOX2. Our data establish distinct differences for SOX2 requirements among placodal sensory organs with similarities between olfactory and lens but not ear placode development, consistent with the unique neurosensory development and molecular properties of the ear.
- MeSH
- apoptóza MeSH
- myši knockoutované MeSH
- myši MeSH
- neurogeneze * MeSH
- nosní sliznice embryologie metabolismus MeSH
- oční čočka embryologie metabolismus MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- vnitřní ucho cytologie embryologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Sox2 is one of the transcription factors responsible for the maintenance of stem cell phenotype. It has been implicated as a marker of stem cells in normal pituitaries and pituitary neuroendocrine tumours. To explore the clinical significance of Sox2 expression in histological sections, we performed immunohistochemical detection of Sox2 in 113 pituitary neuroendocrine tumours from 109 patients with acromegaly. In 11 tumours, we performed double immunostaining for Sox2, annexin A1 and S100 protein. Tumours were characterised using the WHO classification system. Proliferative activity and invasion were assessed. The amount of immunoreactive cells was evaluated and correlated with tumour size and biochemical features (levels of IGF1, GH, prolactin, βTSH). Sox2+ cells were identified in 35/38 normal pituitaries adjacent to the tumours. In 36 tumours (33%), ≥ 1% of the cells expressed Sox2, in 24 cases (22%), Sox2+ cells comprised < 1% and 49 cases (45%) were negative. We found no significant differences between Sox2+ and Sox2- groups with respect to the age, initial levels of GH, IGF1, prolactin, βTSH, tumour size, invasion, proliferative activity or histological features. We observed a positive correlation between Sox2+ cell count and βTSH immunoreactive cells (r = 0.459, p < 0.001) that was further verified by multivariate analysis. Using double stain, the majority of Sox2+ cells coexpressed annexin A1 (average 89%) and S100 protein (average 76.2%) and showed morphological features of folliculo-stellate cells. Sox2+ cells are thus commonly present in growth hormone-producing tumours and normal pituitaries, and their amount does not have any prognostic significance. Most of these cells represent a subpopulation of folliculo-stellate cells, pointing out to their role as a possible stem cell population.
- MeSH
- akromegalie etiologie metabolismus MeSH
- dospělí MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- kmenové buňky metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidský růstový hormon metabolismus MeSH
- nádorové biomarkery metabolismus MeSH
- nádory hypofýzy komplikace patologie MeSH
- neuroendokrinní nádory komplikace patologie MeSH
- transkripční faktory SOXB1 metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Sox2 is one of the core transcription factors maintaining the embryonic stem cells (ES) pluripotency and, also indispensable for cellular reprogramming. However, limited data is available about the DNA methylation of pluripotency genes during lineage-specific differentiations. This study investigated the DNA methylation of Sox2 regulatory region 2 (SRR2) during directed differentiation of mouse ES into neural lineage. ES cells were first grown to form embryoid bodies in suspension which were then dissociated, and cultured in defined medium to promote neural differentiation. Typical neuronal morphology together with the up-regulation of Pax6, neuroepithelial stem cell intermediate filament and β-tubulin III and, down-regulation of pluripotency genes Oct4, Nanog and Sox2 showed the existence of neural phenotype in cells undergoing differentiation. Three CpGs in the core enhancer region of neural-specific SRR2 were individually investigated by direct DNA sequencing post-bisulfite treatment and, found to be unmethylated in differentiated cells at time-points chosen for analysis. This analysis does not limit the possibility of methylation at other CpG sites than those profiled here and/or transient methylation. Hence, similar analyses exploring the DNA methylation at other regions of the Sox2 gene could unravel the onset and transitions of epigenetic signatures influencing the outcome of differentiation pathways and neural development. The data presented here shows that in vitro neural differentiation of embryonic stem cells can be employed to study and characterize molecular regulatory mechanisms governing neurogenesis by applying diverse pharmacological and toxicological agents.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Sarcomas are rare tumors but represent the third most common malignancy in children. The cancer stem cell (CSC) paradigm is well established, and CSCs have been intensively studied in sarcomas in the past decade. SCOPE OF REVIEW: This review summarizes current knowledge on CSCs in sarcomas and provides new perspectives on the role of a deregulated stemness program in sarcomagenesis. MAJOR CONCLUSIONS: Cell surface markers have so far failed to specifically target sarcoma CSCs. Sarcomas likely arise from immature cells that undergo pathological reprogramming. Transcription factor Sox2, which is frequently upregulated in sarcomas, is directly involved in this process, and its crucial role in the acquisition and maintenance of the CSC phenotype has been demonstrated in various sarcomas. GENERAL SIGNIFICANCE: Sox2 is a core functional regulator of the stem-like state and is an outstanding marker of sarcoma CSCs. Fluorescence protein-based reporters of Sox2 expression might provide useful tools for subsequent studies of sarcoma CSCs.
- MeSH
- lidé MeSH
- nádorová transformace buněk metabolismus patologie MeSH
- nádorové kmenové buňky metabolismus patologie MeSH
- sarkom metabolismus patologie MeSH
- transkripční faktory SOXB1 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Most mammals have two sets of teeth (diphyodont) - a deciduous dentition replaced by a permanent dentition; however, the mouse possesses only one tooth generation (monophyodont). In diphyodonts, the replacement tooth forms on the lingual side of the first tooth from the successional dental lamina. This lamina expresses the stem/progenitor marker Sox2 and has activated Wnt/β-catenin signalling at its tip. Although the mouse does not replace its teeth, a transient rudimentary successional dental lamina (RSDL) still forms during development. The mouse RSDL houses Sox2-positive cells, but no Wnt/β-catenin signalling. Here, we show that stabilising Wnt/β-catenin signalling in the RSDL in the mouse leads to proliferation of the RSDL and formation of lingually positioned teeth. Although Sox2 has been shown to repress Wnt activity, overexpression of Wnts leads to a downregulation of Sox2, suggesting a negative-feedback loop in the tooth. In the mouse, the first tooth represses the formation of the replacement, and isolation of the RSDL is sufficient to induce formation of a new tooth germ. Our data highlight key mechanisms that may have influenced the evolution of replacement teeth.This article has an associated 'The people behind the papers' interview.
- MeSH
- miniaturní prasata MeSH
- myši transgenní MeSH
- myši MeSH
- prasata MeSH
- proliferace buněk fyziologie MeSH
- signální dráha Wnt fyziologie MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- zubní zárodek cytologie embryologie MeSH
- zuby cytologie embryologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
