The role of dead-end in germ-cell tumor development

Abstract

Testicular germ-cell tumors occur in human males of all age groups, from infants to men over 50 years old. Most commonly, germ-cell tumors (generally known as testicular cancer) occur in young males between the ages of 15 to 35 years. The tumor tissues are usually histologically diverse, and testicular tumors that occur in the different age groups tend to be of specific histological subtypes. Most germ-cell tumors originate from primordial germ cells during embryonic development, although the progression and eventual detection of the disease occurs decades later in humans. Mouse strains spontaneously develop a specific subtype of testicular germ-cell tumors, the type I germ-cell tumors, and these tumors are similar to the germ-cell tumors (or teratomas) that occur in human infants. Some mouse strains, such as the 129-Ter strain, have extremely high germ-cell tumor incidences, making such strains ideal for genetic and biological studies of germ cell-tumor development. Here a brief overview of the recently identified genetic defect in the Ter strain, inactivation of the dead-end (Dnd1) gene, and the ongoing studies on Dnd1 to understand its role in germ-cell and germ cell-tumor development, are provided.

FIGURE 1

(A) Testis from 129-Ter/Ter;Oct4-GFP strain postnatal day 1 (PN1) testes. PN1 testes observed using reflected light under the stereomicroscope microscope. (B) The same testis was observed for GFP fluorescence by confocal microscopy to observe GFP-expressing germ cells within the seminiferous tubules. Note lack of GFP-expressing germ cells in the 129-Ter/Ter testes. (C) H&E stained histological cross section of the PN1 testes from the 129-Ter/Ter mouse. Arrow indicates clusters of proliferating embryonal carcinoma (EC) cells. (D) Histological cross section, H&E stained, through testicular germ-cell tumor of adult 129-Ter/Ter mouse. The section shows randomly differentiated cell types of the teratoma. (E) Diagram illustrating mouse DND1 isoforms, DND1α and DND1β. DND1α differs from DND1β only at the first 45 and 33 amino acids of the N-terminus, respectively, as indicated by the length of boxes on the right. Box marked RRM indicates RNA recognition motif. Asterisk (*) indicates the position of the stop codon that inactivates DND1 in Ter mice because of the spontaneous mutation.