Neogenin1 is a sonic hedgehog target in medulloblastoma and is necessary for cell cycle progression. Issue 1 (24th July 2013)

• Record Type: Journal Article
• Authors: Milla, Luis A.; Arros, Andrea; Espinoza, Natalie; Remke, Marc; Kool, Marcel; Taylor, Michael D.; Pfister, Stefan M.; Wainwright, Brandon J.; Palma, Verónica
• Is Part Of: International journal of cancer. Volume 134:Issue 1(2014:Jan. 01)
• Page Start: 21
• Page End: 31
• Publication Date: 2013-07-24
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28330
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar growth and alterations cause Shh‐driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1 interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1 expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly regulates the <italic>Neo1</italic> gene acting through an upstream sequence in its promoter both <italic>in vitro</italic> and <italic>in vivo</italic> in granule neuron precursor cells. We also identified and characterized a functional Gli‐binding site in the first intron of the human <italic>NEO1</italic> gene. Gene expression profiling of more than 300 MB shows that <italic>NEO1</italic> is indeed upregulated in SHH tumors compared to the other MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line, because a loss of function of <italic>NEO1</italic> arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a novel downstream effector of the Shh pathway in MB and a possible therapeutic target.</p> </abstract>