ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

Bikeye, Sandra-Nadia Ngwabyt; Colin, Carole; Marie, Yannick; Vampouille, Raphaël; Ravassard, Philippe; Rousseau, Audrey; Boisselier, Blandine; Idbaïh, Ahmed; Calvo, Charles‐Félix; Leuraud, Pascal; Lassalle, Myriam; Hallani, Soufiane El; Delattre, Jean‐Yves; Sanson, Marc

doi:10.1186/1475-2867-10-1

Cited by 80 publications

(86 citation statements)

References 12 publications

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“…Indeed, we found that ASPM is expressed at high levels in all MB tissues and cell lines, and in normal fetal cerebellum, but at very low levels in normal adult cerebellum. This substantial differential expression between proliferating tissues (malignant and normal) and normal adult parenchyma fits well with the potential mitotic role of ASPM, and suggests that ASPM may be an attractive therapeutic target in MBs, just as recently indicated for glioblastomas [13].…”

Section: Discussionsupporting

confidence: 72%

Expression profile of frizzled receptors in human medulloblastomas

et al. 2011

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Secreted WNT proteins signal through ten receptors of the frizzled (FZD) family. Because of the relevance of the WNT/β-catenin (CTNNB1) signaling pathway in medulloblastomas (MBs), we investigated the expression of all ten members of the FZD gene family (FZD1-10) in 17 human MBs, four MB cell lines and in normal human cerebellum, using real-time PCR. We found that FZD2 transcript was over-expressed in all MBs and MB cell lines. Western blot analysis confirmed the expression of FZD2 at the protein level. Moreover, the levels of FZD2 transcript were found to correlate with those of ASPM transcript, a marker of mitosis essential for mitotic spindle function. Accordingly, ASPM mRNA was expressed at a very low level in the adult, post-mitotic, human cerebellum, at higher levels in fetal cerebellum and at highest levels in MB tissues and cell lines. Unlike FZD2, the other FZDs were overexpressed (e.g., FZD1, FZD3 and FZD8) or underexpressed (e.g., FZD7, FZD9 and FZD10) in a case-restricted manner. Interestingly, we did not find any nuclear immuno-reactivity to CTNNB1 in four MBs over-expressing both FZD2 and other FZD receptors, confirming the lack of nuclear CTNNB1 staining in the presence of increased FZD expression, as in other tumor types. Overall, our results indicate that altered expression of FZD2 might be associated with a proliferative status, thus playing a role in the biology of human MBs, and possibly of cerebellar progenitors from which these malignancies arise.

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Section: Discussionsupporting

confidence: 72%

Expression profile of frizzled receptors in human medulloblastomas

et al. 2011

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“…Moreover, mouse models of MCPH3 and MCPH5 displayed an increased tumor risk and/or blood abnormalities (anemia, leucopenia) [35,36]. It is likely that the deceased sister of the index patient who also had severe microcephaly at birth and intellectual disability, carried the p.R438H / p.D955Afs*112 mutations of the WDR62 gene.…”

Section: Discussionmentioning

confidence: 99%

Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

Farag

Froehler

Oexle³

et al. 2013

Orphanet J Rare Dis

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BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.Methods/resultsWe characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient’s immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.ConclusionWe propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.

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“…FoxO activity negatively regulates Aspm expression while promoting expression of Wnt pathway antagonists in neural progenitor cells, suggesting a mechanism to link Aspm expression and Wnt activity (Paik et al 2009). Additionally, ASPM overexpression, like many Wnt-activating components, is associated with increased cell proliferation and tumor development, supporting a common effect on proliferation (Kouprina et al 2005;Hagemann et al 2008;Klaus and Birchmeier 2008;Lin et al 2008;Bikeye et al 2010;Vulcani-Freitas et al 2011). On the other hand, decreased expression of the schizophrenia risk gene Disc1 or its binding partner, Dixdc1, results in diminished Wnt signaling activity with accompanying deficits in embryonic and adult cortical neurogenesis (Mao et al 2009;Singh et al 2010).…”

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confidence: 93%

ASPM regulates Wnt signaling pathway activity in the developing brain

Buchman¹,

Durak²,

Tsai³

2011

Genes Dev.

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Autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder in which patients display significantly reduced brain size. Mutations in Abnormal Spindle Microcephaly (ASPM) are the most common cause of MCPH. Here, we investigate the underlying functions of Aspm in brain development and find that Aspm expression is critical for proper neurogenesis and neuronal migration. The Wnt signaling pathway is known for its roles in embryogenesis, and genome-wide siRNA screens indicate that ASPM is a positive regulator of Wnt signaling. We demonstrate that knockdown of Aspm results in decreased Wnt-mediated transcription, and that expression of stabilized b-catenin can rescue this deficit. Finally, coexpression of stabilized b-catenin can rescue defects observed upon in vivo knockdown of Aspm. Our findings provide an impetus to further explore Aspm's role in facilitating Wnt-mediated neurogenesis programs, which may contribute to psychiatric illness etiology when perturbed.

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ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

Cited by 80 publications

References 12 publications

Expression profile of frizzled receptors in human medulloblastomas

Expression profile of frizzled receptors in human medulloblastomas

Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

ASPM regulates Wnt signaling pathway activity in the developing brain

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