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The Transcription Factor Cux1 in Cerebellar Granule Cell Development and Medulloblastoma Pathogenesis

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Abstract

Cux1, also known as Cutl1, CDP or Cut is a homeodomain transcription factor implicated in the regulation of normal and oncogenic development in diverse peripheral tissues and organs. We studied the expression and functional role of Cux1 in cerebellar granule cells and medulloblastoma. Cux1 is robustly expressed in proliferating granule cell precursors and in postmitotic, migrating granule cells. Expression is lost as postmigratory granule cells mature. Moreover, Cux1 is also strongly expressed in a well-established mouse model of medulloblastoma. In contrast, expression of CUX1 in human medulloblastoma tissue samples is lower than in normal fetal cerebellum. In these tumors, CUX1 expression tightly correlates with a set of genes which, when mapped on a global protein-protein interaction dataset, yields a tight network that constitutes a cell cycle control signature and may be related to p53 and the DNA damage response pathway. Antisense-mediated reduction of CUX1 levels in two human medulloblastoma cell lines led to a decrease in proliferation and altered motility. The developmental expression of Cux1 in the cerebellum and its action in cell lines support a role in granule cell and medulloblastoma proliferation. Its expression in human medulloblastoma shifts that perspective, suggesting that CUX1 is part of a network involved in cell cycle control and maintenance of DNA integrity. The constituents of this network may be rational targets to therapeutically approach medulloblastomas.

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Acknowledgments

We are grateful to Dr. D. Hatfield, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA for the generous gift of the pU6m4 silencing vector. We would like to thank D. Krauß and F. Neuhalfen for their help with animal husbandry.

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  1. Alexander Glassmann

    Present address: Projektgruppe EPN-Technologie, Life Science Inkubator GmbH, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany

Authors and Affiliations

  1. Anatomisches Institut, Anatomie & Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Nussallee 10, 53115, Bonn, Germany

    Sabine Topka, Alexander Glassmann, Gunnar Weisheit & Karl Schilling

  2. Center for Neuropathology, Ludwig-Maximilians-University, Feodor-Lynen-Strasse 23, 81377, Munich, Germany

    Ulrich Schüller

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Topka, S., Glassmann, A., Weisheit, G. et al. The Transcription Factor Cux1 in Cerebellar Granule Cell Development and Medulloblastoma Pathogenesis. Cerebellum 13, 698–712 (2014). https://doi.org/10.1007/s12311-014-0588-x

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