Expression of the neurogenic basic helix-loop-helix transcription factor NEUROG1 identifies a subgroup of medulloblastomas not expressing ATOH1

摘要: Medulloblastomas (MBs) are malignant tumors of the cerebellum. They commonly affect children, no more than 30% occurring in individuals older 16 years, and considered embryonic since they originate from precursors present during cerebellar development. In particular, MBs may derive granule cell (GCPs), which form a layer proliferating committed cells subpial surface cerebellum fetal postnatal period. Neuroepithelial ventricular zone (CVZ), displaced around midline neuroectodermal tube, constitute other origin MBs.1 The idea that have double is molecularly supported by expression neurotrophin receptor p75NTR,2 calcium-binding protein calbin-din-D28k,3 human atonal homolog 1 (ATOH1) gene distinct subsets these tumors. ATOH1 basic helix-loop-helix (bHLH) transcription factor (TF), its mouse homolog, Math1, exclusively expressed GCPs Math1 seems necessary to uncommitted CVZ differentiate first as finally postmitotic, cells.4 only subgroup MBs, suggesting not all GCPs.5–7 Interestingly, with transcript located hemispheres rather vermis, should be expected if effectively GCPs.8 Since expressing afflict almost adult patients, MBs. On hand, there molecular marker, functionally analogous ATOH1, identifying deriving precursor CVZ. Indeed, calbindin-D28k, marker originating CVZ, protein, it also mature neurons. contrast, neurogenin-1 (NEUROG1) proneural bHLH TF functions determinant neuronal identity subset interneuronal murine spinal cord pattern complementary Math1.9 Its role development, any, was yet investigated, but NEUROG1, detected associated poor prognosis.10 Moreover, development brain, Ngn1 transiently expressed, detectable nervous tissue, reinforcing similarity Math1.11 A histogenesis activation different proliferative signaling pathways, SHH WNT pathways. glycoprotein secreted Purkinje cortex interacts transmembrane PTCH GCPs, stimulating their proliferation. mutations were found sporadic Gorlin syndrome, an autosomal-dominant cancer syndrome characterized propensity develop multiple neoplasms, including basal carcinomas MBs. The final common effector SHH-dependent pathway GLI1.12 models, Gli1 plays important formation MBs,13 even though alteration does appear general requirement.14 On neuroepithelial unclear.15,16 MB conserve many characters origin, likely play relevant progenitors pathway, on contrary, pivotal pathogenesis this latter subgroup. Dysregulation WNT-dependent has been involved Turcot another CNS familial polyposis colon.17 Many proteins corresponding frizzled-homolog receptors (FZDs) described, much less known about activated when ligands bind FZDs, causing stabilization β-catenin translocation into nucleus. nucleus, activates number oncogenic targets, MYC, although transcriptional β-catenin– independent mechanism for MYC overexpression MBs.18 Here, we examined mRNA NEUROG1 embryonal addition, investigated GLI1 activation, nuclear staining, mutations, and/or indicators activation. A link between pathways assessed. Finally, smaller series analyzed OTX2, shown further positive originated GCPs.19