title: Germ cell pluripotency, premature differentiation and susceptibility to testicular teratomas in mice.
abstract: Testicular teratomas result from anomalies in germ cell development during embryogenesis. In the 129 family of inbred strains of mice, teratomas initiate around embryonic day (E) 13.5 during the same developmental period in which female germ cells initiate meiosis and male germ cells enter mitotic arrest. Here, we report that three germ cell developmental abnormalities, namely continued proliferation, retention of pluripotency, and premature induction of differentiation, associate with teratoma susceptibility. Using mouse strains with low versus high teratoma incidence (129 versus 129-Chr19(MOLF/Ei)), and resistant to teratoma formation (FVB), we found that germ cell proliferation and expression of the pluripotency factor Nanog at a specific time point, E15.5, were directly related with increased tumor risk. Additionally, we discovered that genes expressed in pre-meiotic embryonic female and adult male germ cells, including cyclin D1 (Ccnd1) and stimulated by retinoic acid 8 (Stra8), were prematurely expressed in teratoma-susceptible germ cells and, in rare instances, induced entry into meiosis. As with Nanog, expression of differentiation-associated factors at a specific time point, E15.5, increased with tumor risk. Furthermore, Nanog and Ccnd1, genes with known roles in testicular cancer risk and tumorigenesis, respectively, were co-expressed in teratoma-susceptible germ cells and tumor stem cells, suggesting that retention of pluripotency and premature germ cell differentiation both contribute to tumorigenesis. Importantly, Stra8-deficient mice had an 88% decrease in teratoma incidence, providing direct evidence that premature initiation of the meiotic program contributes to tumorigenesis. These results show that deregulation of the mitotic-meiotic switch in XY germ cells contributes to teratoma initiation.
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA. heaney@bcm.edu
authors.forename: Jason D
authors.initials: JD
authors.lastname: Heaney
authors.forename: Ericka L
authors.initials: EL
authors.lastname: Anderson
authors.forename: Megan V
authors.initials: MV
authors.lastname: Michelson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Zechel
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Conrad
authors.forename: David C
authors.initials: DC
authors.lastname: Page
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Nadeau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D020732:Cytogenetic Analysis; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005854:Germ Cells / Q000166:cytology*; D006652:Histological Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011506:Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013045:Species Specificity; D013724:Teratoma / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530105:Ccnd1 protein, mouse; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D011506:Proteins; C102019:Stra8 protein, mouse; D019938:Cyclin D1