Abstract
A spontaneous mutation leading to the formation of congenital ovarian and testicular tumors was detected in the WKY/Ztm rat strain. The histological evaluation revealed derivatives from all three germ layers, thereby identifying these tumors as teratomas. Teratocarcinogenesis was accompanied by infertility and the underlying mutation was termed ter. Linkage analysis of 58 (WKY-ter×SPRD-Cu3) F2 rats associated the ter mutation with RNO18 (LOD = 3.25). Sequencing of candidate genes detected a point mutation in exon 4 of the dead-end homolog 1 gene (Dnd1), which introduces a premature stop codon assumed to cause a truncation of the Dnd1 protein. Genotyping of the recessive ter mutation revealed a complete penetrance of teratocarcinogenesis and infertility in homozygous ter rats of both genders. Morphologically non-tumorous testes of homozygous ter males were reduced in both size and weight. This testicular malformation was linked to a lack of spermatogenesis using immunohistochemical and histological staining. Our WKY-Dnd1ter/Ztm rat is a novel animal model to investigate gonadal teratocarcinogenesis and the molecular mechanisms involved in germ cell development of both genders.
Highlights
Tumors classified as germ cell tumors (GCTs) are derived from cells belonging to the germline and are a heterogeneous group of neoplasms with varying histopathological and clinical manifestations [1]
Recent genome-wide association studies linked six gene loci to the development of testicular germ cell tumors (TGCTs): KITLG, SPRY4 and BAK1 are involved in the KIT pathway, TERT-CLPTM1L and ATF7IP in telomerase regulation, and DMRT1 in sex determination [7,8,9]
Teratocarcinomas in the WKY strain We established a coisogenic segregating inbred WKY strain that carries a mutation referred to as ter leading to germ cell tumors (GCT) in both testes and ovaries (Fig. 1A)
Summary
Tumors classified as germ cell tumors (GCTs) are derived from cells belonging to the germline and are a heterogeneous group of neoplasms with varying histopathological and clinical manifestations [1]. Human germ cell tumors (GCT) can be observed in all age groups, ranging from infancy to adulthood, and are frequently diagnosed at a young age [2,3]. The molecular principles underlying ovarian germ cell tumor (OGCT) development remain poorly understood [4,5]. In the testes mutations in TP53, KIT, KRAS/NRAS, and BRAF genes can contribute to the neoplastic transformation of germ cell precursors [6]. Recent genome-wide association studies linked six gene loci to the development of testicular germ cell tumors (TGCTs): KITLG, SPRY4 and BAK1 are involved in the KIT pathway, TERT-CLPTM1L and ATF7IP in telomerase regulation, and DMRT1 in sex determination [7,8,9]. Various male reproductive disorders, including infertility and TGCTs, are thought to result from similar disruptions during fetal development and have been grouped together in the so-called testicular dysgenesis syndrome (TDS) [11,12]
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