SOX9 induces and maintains neural stem cells

Scott, Charlotte Elizabeth; Wynn, Sarah; Sesay, Abdul Karim; Cruz, Cristina; Cheung, Martin; Gómez-Gaviro, Marı́a Victoria; Booth, Sarah; Gao, Bo; Cheah, Kathryn S.E.; Lovell-Badge, Robin; Briscoe, James

doi:10.1038/nn.2646

Cited by 315 publications

(313 citation statements)

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“…Expression studies have shown that SOX9 is expressed by neuroepithelial cells in the ventricular zone of the developing spinal cord, by oligodendrocytes and by astrocytes but not by neurons (Stolt et al, 2003). Knocking out Sox9 in the developing mouse spinal cord results in perinatal lethality, decreased numbers of oligodendrocyte progenitors and astrocytes and an increased number of motor neurons (Stolt et al, 2003) and neuroblasts (Scott et al, 2010). MicroRNA studies also suggest that SOX9 is gliogenic, promoting neural stem cells to adopt an astrocyte or oligodendrocyte fate (Cheng et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI.

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Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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“…Furthermore, the 5AdC-induced SKNAS sphere culture grown in the sphere-forming condition without 5AdC for 1.5 y (day 592) expressed higher levels of SOX2, CD133, and neural crest stem cell markers (p75 NTR , SOX9, SOX10, SLUG, Musashi-1) compared with the non-drug-treated sphere culture and the monolayer counterpart (Fig. 1C), suggesting that these SKNAS spheres express a phenotype more similar to neural crest stem cells (14)(15)(16)(17)(18). Immunocytochemical assay further showed that the 5AdC-induced SKNAS spheres at Fig.…”

Section: Short-term Treatments With Epigenetic Modifiers Enhance the mentioning

confidence: 97%

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Ikegaki

Shimada

Fox

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell-like NB cells that are phenotypically stable for more than a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSCs (iCSCs). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected s.c. into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSCs metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated large-cell NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, whereas the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest both that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells.tumor initiating cells | prominent nucleoli N euroblastoma (NB) is the most common extracranial pediatric malignancy. Although some NBs are easily treatable, nearly 50% of the tumors exhibit aggressive behavior. The International Neuroblastoma Risk Group Classification is used to classify NB at diagnosis (1). High-risk NBs are associated with older age, advanced stages, unfavorable histologic features, widespread tumor dissemination, and poor long-term survival (1). Current treatment for these NBs includes high-dose chemotherapy or myeloablative cytotoxic therapy with autologous hematopoietic stem cell transplantation (2). However, late relapse is often seen despite achieving complete clinical remission. A subset of high-risk NBs, which is refractory to current frontline therapy designed for high-risk NB, is termed ultra-high-risk NB (3, 4).NB is histopathologically defined as neuroblastic tumors with less than 50% Schwannian stromal components. On the basis of the degree of neuronal differentiation, NB is further divided into undifferentiated (UD), poorly differentiated, and differentiating subtypes (5, 6). A unique histological subset of NBs within the UD and poorly differentiated subtypes has also been identified (7,8). These tumors are uniformly composed of large cells with sharply outlined nuclear membranes and one to four prominent nucleoli and are referred...

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“…To address whether motif enrichment predicts TF binding and examine the function of enhancer-bound TFs, we chose to focus on the NFI family, since the NFI motif was the most prevalent in quiescent NSC enhancers, and these factors were not previously known to regulate NSC biology, whereas the functions of Sox and bHLH factors have already been extensively studied in these cells (Bylund et al 2003;Ligon et al 2007;Scott et al 2010;Castro et al 2011). Our RNA-seq, immunocytochemistry, and Western blot data showed that the four members of the NFI family (NFIA, NFIB, NFIC, and NFIX) are expressed in both proliferating and quiescent NSCs, but NFIX is up-regulated when NS cells become quiescent (the nuclear protein ratio in quiescent cells/proliferating cells is 226%), while NFIA, NFIB, and NFIC are down-regulated or unchanged (64%, 51%, and 87%, respectively) ( Fig.…”

Section: Widespread Binding Of Nfi Tfs To Quiescent Ns Cell Enhancersmentioning

confidence: 99%

Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

Martynoga¹,

et al. 2013

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The majority of neural stem cells (NSCs) in the adult brain are quiescent, and this fraction increases with aging. Although signaling pathways that promote NSC quiescence have been identified, the transcriptional mechanisms involved are mostly unknown, largely due to lack of a cell culture model. In this study, we first demonstrate that NSC cultures (NS cells) exposed to BMP4 acquire cellular and transcriptional characteristics of quiescent cells. We then use epigenomic profiling to identify enhancers associated with the quiescent NS cell state. Motif enrichment analysis of these enhancers predicts a major role for the nuclear factor one (NFI) family in the gene regulatory network controlling NS cell quiescence. Interestingly, we found that the family member NFIX is robustly induced when NS cells enter quiescence. Using genome-wide location analysis and overexpression and silencing experiments, we demonstrate that NFIX has a major role in the induction of quiescence in cultured NSCs. Transcript profiling of NS cells overexpressing or silenced for Nfix and the phenotypic analysis of the hippocampus of Nfix mutant mice suggest that NFIX controls the quiescent state by regulating the interactions of NSCs with their microenvironment.

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SOX9 induces and maintains neural stem cells

Cited by 315 publications

References 50 publications

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

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