title: Neogenin1 is a Sonic Hedgehog target in medulloblastoma and is necessary for cell cycle progression.
abstract: 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 Neo1 gene acting through an upstream sequence in its promoter both in vitro and in vivo in granule neuron precursor cells. We also identified and characterized a functional Gli-binding site in the first intron of the human NEO1 gene. Gene expression profiling of more than 300 MB shows that NEO1 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 NEO1 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.
authors.affiliation: Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile; FONDAP Center for Genome Regulation, Santiago, Chile.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Milla
authors.forename: Andrea
authors.initials: A
authors.lastname: Arros
authors.forename: Natalie
authors.initials: N
authors.lastname: Espinoza
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
authors.forename: Verónica
authors.initials: V
authors.lastname: Palma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome
chemical_list: D053823:Hedgehog Proteins; D008565:Membrane Proteins; C509239:SHH protein, human; C091279:neogenin
keywords: Gli; Neogenin 1; Sonic Hedgehog; cancer; medulloblastoma