title: Tis21 knock-out enhances the frequency of medulloblastoma in Patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons.
abstract: A failure in the control of proliferation of cerebellar granule neuron precursor cells (GCPs), located in the external granular layer (EGL) of the cerebellum, gives rise to medulloblastoma. To investigate the process of neoplastic transformation of GCPs, we generated a new medulloblastoma model by crossing Patched1 heterozygous mice, which develop medulloblastomas with low frequency, with mice lacking the Tis21 gene. Overexpression of Tis21 is known to inhibit proliferation and trigger differentiation of GCPs; its expression decreases in human medulloblastomas. Double-knock-out mice show a striking increase in the frequency of medulloblastomas and hyperplastic EGL lesions, formed by preneoplastic GCPs. Tis21 deletion does not affect the proliferation of GCPs but inhibits their differentiation and, chiefly, their intrinsic ability to migrate outside the EGL. This defect of migration may represent an important step in medulloblastoma formation, as GCPs, remaining longer in the EGL proliferative niche, may become more prone to transformation. By genome-wide analysis, we identified the chemokine Cxcl3 as a target of Tis21. Cxcl3 is downregulated in Tis21-null GCPs of EGL and lesions; addition of Cxcl3 to cerebellar slices rescues the defective migration of Tis21-null GCPs and, remarkably, reduces the area of hyperplastic lesions. As Tis21 activates Cxcl3 transcription, our results suggest that Tis21 induces migration of GCPs through Cxcl3, which may represent a novel target for medulloblastoma therapy.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.forename: Irene
authors.initials: I
authors.lastname: Cinà
authors.forename: Manuela
authors.initials: M
authors.lastname: Ceccarelli
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.forename: Luca
authors.initials: L
authors.lastname: Leonardi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.forename: Marco
authors.initials: M
authors.lastname: De Bardi
authors.forename: Concezio
authors.initials: C
authors.lastname: Di Rocco
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001973:Bromodeoxyuridine; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D002531:Cerebellum / Q000166:cytology*; D019743:Chemokines, CXC / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors; D005838:Genotype; D006579:Heterozygote; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009474:Neurons / Q000502:physiology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D019743:Chemokines, CXC; D017874:Immediate-Early Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C500943:Atoh1 protein, mouse; C489435:Btg2 protein, mouse; C577095:Cxcl3 protein, mouse; C000606236:PTCH1 protein, human; C000606240:Ptch1 protein, mouse