BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma.
Medulloblastomas are the most common malignant pediatric brain tumor and have been divided into four major molecular subgroups. Animal models that mimic the principal molecular aberrations of these subgroups will be important tools for preclinical studies and allow greater understanding of medulloblastoma biology. We report a new transgenic model of medulloblastoma that possesses a unique combination of desirable characteristics including, among others, the ability to incorporate multiple and variable genes of choice and to produce bioluminescent tumors from a limited number of somatic cells within a normal cellular environment. This model, termed BarTeL, utilizes a Barhl1 homeobox gene promoter to target expression of a bicistronic transgene encoding both the avian retroviral receptor TVA and an eGFP-Luciferase fusion protein to neonatal cerebellar granule neuron precursor (cGNP) cells, which are cells of origin for the sonic hedgehog (SHH) subgroup of human medulloblastomas. The Barhl1 promoter-driven transgene is expressed strongly in mammalian cGNPs and weakly or not at all in mature granule neurons. We efficiently induced bioluminescent medulloblastomas expressing eGFP-luciferase in BarTeL mice by infection of a limited number of somatic cGNPs with avian retroviral vectors encoding the active N-terminal fragment of SHH and a stabilized MYCN mutant. Detection and quantification of the increasing bioluminescence of growing tumors in young BarTeL mice was facilitated by the declining bioluminescence of their uninfected maturing cGNPs. Inclusion of eGFP in the transgene allowed enriched sorting of cGNPs from neonatal cerebella. Use of a single bicistronic avian vector simultaneously expressing both Shh and Mycn oncogenes increased the medulloblastoma incidence and aggressiveness compared to mixed virus infections. Bioluminescent tumors could also be produced by ex vivo transduction of neonatal BarTeL cerebellar cells by avian retroviruses and subsequent implantation into nontransgenic cerebella. Thus, BarTeL mice provide a versatile model with opportunities for use in medulloblastoma biology and therapeutics.
Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Radiology, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Gregory M
http://orcid.org/0000-0003-4831-575X
GM
Shackleford
Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Xiang-He
XH
Shi
Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Radiology, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Kimberly S
KS
Swanson
Department of Radiology, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Min Y
MY
Mahdi
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Ignacio
I
Gonzalez-Gomez
Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Shahab
S
Asgharzadeh
Department of Pathology, City of Hope National Medical Center, Duarte, California, United States of America.
Massimo
M
D'Apuzzo
Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Anat
A
Erdreich-Epstein
Department of Radiology, The Saban Research Institute, Children's Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Biomedical Engineering, University of Southern California, Los Angeles, California, United States of America.
Rex A
RA
Moats
D000818:Animals; D000831:Animals, Newborn; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018703:Founder Effect; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism
D030161:Avian Proteins; C485866:Barhl1 protein, mouse; D053823:Hedgehog Proteins; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D009419:Nerve Tissue Proteins; D011991:Receptors, Virus; D012097:Repressor Proteins; C465570:Shh protein, mouse; C088745:Tva receptor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008156:Luciferases