OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells

Bai, Ren Yuan; Staedtke, Verena; Lidov, Hart G.W.; Eberhart, Charles G.; Riggins, Gregory J.

doi:10.1158/0008-5472.can-12-0614

Cited by 34 publications

(29 citation statements)

References 49 publications

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“…The suppressor activity of Otx2 has been previously documented in the cerebellum and the retina, and during myogenesis and neurogenesis (Bai et al, 2012;Nishida et al, 2003;Puelles et al, 2006Puelles et al, , 2003. Sox2 and Otx2 are able to interact directly via their HMG and homeobox DNA-binding domains, respectively (Danno et al, 2008), and Otx2 has been shown to suppress the expression of Sox2 during retinal differentiation (Nishihara et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

et al. 2015

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Transcriptional regulatory networks are essential during the formation and differentiation of organs. The transcription factor N-myc is required for proper morphogenesis of the cochlea and to control correct patterning of the organ of Corti. We show here that the Otx2 gene, a mammalian ortholog of the Drosophila orthodenticle homeobox gene, is a crucial target of N-myc during inner ear development. Otx2 expression is lost in N-myc mouse mutants, and N-myc misexpression in the chick inner ear leads to ectopic expression of Otx2. Furthermore, Otx2 enhancer activity is increased by N-myc misexpression, indicating that N-myc may directly regulate Otx2. Inactivation of Otx2 in the mouse inner ear leads to ectopic expression of prosensory markers in non-sensory regions of the cochlear duct. Upon further differentiation, these domains give rise to an ectopic organ of Corti, together with the respecification of non-sensory areas into sensory epithelia, and the loss of Reissner's membrane. Therefore, the Otx2-positive domain of the cochlear duct shows a striking competence to develop into a mirrorimage copy of the organ of Corti. Taken together, these data show that Otx2 acts downstream of N-myc and is essential for patterning and spatial restriction of the sensory domain of the mammalian cochlea.

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Section: Discussionmentioning

confidence: 99%

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

et al. 2015

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“…Mouse glioma cell line GL261 cells were kindly provided by Dr. Michael Lim's laboratory at the Johns Hopkins University in 2009 and human medulloblastoma cell line D425Med (D425) was obtained from the Duke University Brain Tumor Center without further authentication (3, 15). GL261 and D425 cells were maintained in DMEM media supplemented with 10% fetal bovine serum and antibiotics at 37°C in humidified air containing 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model

Bai

Staedtke

Wanjiku

et al. 2015

Clinical Cancer Research

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Purpose Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different MBZ polymorphs (A, B and C) exist and a detailed assessment of the brain penetration, pharmacokinetics and anti-tumor properties of each individual MBZ polymorph is necessary to improve mebendazole-based brain cancer therapy. Experimental Design and Results In this study, various marketed and custom-formulated MBZ tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of MBZ polymorphs and two main metabolites were analyzed by LC-MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Both, polymorph B and C, reached concentrations in the brain that exceeded the IC50 in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC0-24h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice. Conclusion Among MBZ polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with less side effects and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar.

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“…We focused on dmbx1, which we hypothesize functions to promote cell cycle exit (Wong et al, 2010) and its putative interaction with vsx2. Vertebrate Dmbx1 is thought to function as a transcriptional repressor (Bai et al, 2012;Berry et al, 2006;Kimura et al, 2005;Yao and Kessler, 2001), but its targets are largely unknown. The vertebrate Vsx2 gene is required for embryonic cells to maintain a proliferative RPC identity (Burmeister et al, 1996;Horsford et al, 2005), in part through its function in repressing genes that would otherwise specify different retinal cell fates Vitorino et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Mutual antagonism of the paired-type homeobox genes, vsx2 and dmbx1, regulates retinal progenitor cell cycle exit upstream of ccnd1 expression

Wong

Power

Miles

et al. 2015

Developmental Biology

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Understanding the mechanisms that regulate the transition between the proliferative and a post-mitotic state of retinal progenitor cells (RPCs) is key to advancing our knowledge of retinal growth and maturation. In the present study we determined that during zebrafish embryonic retinal neurogenesis, two paired-type homeobox genes - vsx2 and dmbx1 - function in a mutually antagonistic manner. We demonstrate that vsx2 gene expression requires active Fgf signaling and that this in turn suppresses dmbx1 expression and maintains cells in an undifferentiated, proliferative RPC state. This vsx2-dependent RPC state can be prolonged cell-autonomously by knockdown of dmbx1, or it can be suppressed prematurely by the over-expression of dmbx1, which we show can inhibit vsx2 expression and lead to precocious neuronal differentiation. dmbx1 loss of function also results in altered expression of canonical cell cycle genes, and in particular up-regulation of ccnd1, which correlates with our previous finding of a prolonged RPC cell cycle. By knocking down ccnd1 and dmbx1 simultaneously, we show that RPCs can overcome this phenotype to exit the cell cycle on time and differentiate normally into retinal neurons. Collectively, our data provide novel insight into the mechanism that enables RPCs to exit the cell cycle through a previously unrecognized antagonistic interaction of two paired-type homeobox genes that are central regulators of an Fgf-vsx2-dmbx1-ccnd1 signaling axis.

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OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells

Cited by 34 publications

References 49 publications

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model

Mutual antagonism of the paired-type homeobox genes, vsx2 and dmbx1, regulates retinal progenitor cell cycle exit upstream of ccnd1 expression

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