Browsing by Author "Northcott, Paul A."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    The RNA-Binding Protein Musashi1 Affects Medulloblastoma Growth via a Network of Cancer- Related Genes and Is an Indicator of Poor Prognosis
    (2012-11) Vo, Dat T.; Subramaniam, Dharmalingam; Remke, Marc; Burton, Tarea L.; Uren, Philip J.; Gelfond, Jonathan A.; Abreu, Raquel de Sousa; Burns, Suzanne C.; Qiao, Mei; Suresh, Uthra; Korshunov, Andrey; Dubuc, Adrian M.; Northcott, Paul A.; Smith, Andrew D.; Pfister, Stefan M.; Taylor, Michael D.; Janga, Sarath Chandra; Anant, Shrikant; Vogel, Christine; Penalva, Luiz O. F.
    Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target.
  • Thumbnail Image
    Item
    Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome
    (Springer Nature, 2024-12-05) Eom, Tae-Yeon; Schmitt, J. Eric; Li, Yiran; Davenport, Christopher M.; Steinberg, Jeffrey; Bonnan, Audrey; Alam, Shahinur; Ryu, Young Sang; Paul, Leena; Hansen, Baranda S.; Khairy, Khaled; Pelletier, Stephane; Pruett-Miller, Shondra M.; Roalf, David R.; Gur, Raquel E.; Emanuel, Beverly S.; McDonald-McGinn, Donna M.; Smith, Jesse N.; Li, Cai; Christie, Jason M.; Northcott, Paul A.; Zakharenko, Stanislav S.; Medical and Molecular Genetics, School of Medicine
    Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1+/- mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.