title: Misexpression of cyclin D1 in embryonic germ cells promotes testicular teratoma initiation.
abstract: Testicular teratomas result from anomalies in embryonic germ cell development. In the 129 family of inbred mouse strains, teratomas arise during the same developmental period that male germ cells normally enter G1/G0 mitotic arrest and female germ cells initiate meiosis (the mitotic:meiotic switch). Dysregulation of this switch associates with teratoma susceptibility and involves three germ cell developmental abnormalities seemingly critical for tumor initiation: delayed G1/G0 mitotic arrest, retention of pluripotency, and misexpression of genes normally restricted to embryonic female and adult male germ cells. One misexpressed gene, cyclin D1 (Ccnd1), is a known regulator of cell cycle progression and an oncogene in many tissues. Here, we investigated whether Ccnd1 misexpression in embryonic germ cells is a determinant of teratoma susceptibility in mice. We found that CCND1 localizes to teratoma-susceptible germ cells that fail to enter G1/G0 arrest during the mitotic:meiotic switch and is the only D-type cyclin misexpressed during this critical developmental time frame. We discovered that Ccnd1 deficiency in teratoma-susceptible mice significantly reduced teratoma incidence and suppressed the germ cell proliferation and pluripotency abnormalities associated with tumor initiation. Importantly, Ccnd1 expression was dispensable for somatic cell development and male germ cell specification and maturation in tumor-susceptible mice, implying that the mechanisms by which Ccnd1 deficiency reduced teratoma incidence were germ cell autonomous and specific to tumorigenesis. We conclude that misexpression of Ccnd1 in male germ cells is a key component of a larger pro-proliferative program that disrupts the mitotic:meiotic switch and predisposes 129 inbred mice to testicular teratocarcinogenesis.
authors.affiliation: a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.
authors.forename: Denise G
authors.initials: DG
authors.lastname: Lanza
authors.affiliation: a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Dawson
authors.affiliation: b Department of Pathology , MD Anderson Cancer Center, The University of Texas , Houston , TX , USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Rao
authors.affiliation: a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.|c Dan L Duncan Cancer Center, Baylor College of Medicine , Houston , TX , USA.|d Center For Reproductive Medicine, Baylor College of Medicine , Houston , TX , USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Heaney
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D000066473:Embryonic Germ Cells / Q000378:metabolism*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D008540:Meiosis; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008938:Mitosis; D012708:Sertoli Cells / Q000378:metabolism; D013724:Teratoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D013736:Testicular Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; D019938:Cyclin D1
keywords: Cyclin D1 (Ccnd1); development; germ cells; pluripotency; teratomas