129/Sv mice—a model system for studying germ cell biology and
Lily I. Jiang, Joseph H. Nadeau
Department of Genetics, Case Western Reserve University, School of Medicine, 10900 Euclid Ave., Cleveland, Ohio 44106, USA
Received: 18 September 2000 / Accepted: 4 October 2000
Abstract. Some forms of testicular germ cell tumors (TGCTs)
arise from primordial germ cells (PGCs) during fetal development.
In both humans and mice, genetic control of susceptibility is com-
plex, involving both Mendelian and polygenic factors. Identifica-
tion and characterization of TGCT genes will provide insight not
only into the basis for inherited susceptibility, but also into the
genetic control of the development of the PGC lineage. Recent
work has revealed the identity of several susceptibility genes that
are inherited as Mendelian traits, the chromosomal location of
yet-to-be identified TGCT susceptibility genes, as well as clues to
the nature of developmental pathways involved in tumorigenesis.
In this review we summarize current understanding of the biology
and genetics of TGCTs in mice and discuss the relevance of this
work to testicular cancer in humans.
The 129/Sv inbred strain was the foundation for establishing em-
bryonic stem (ES) cell cultures. The ability to manipulate these
cells in vitro revolutionized mouse genetics by permitting inten-
tional mutations in specific genes through genetic engineering
(Baribault and Kemler 1989; Bradley et al. 1992, 1998). L.C.
Stevens’ pioneering work on embryonic carcinoma (EC) cells
found in testicular germ cell tumors (TGCTs) in 129/Sv mice
contributed importantly to methodologies for working with ES
cells (Stevens and Hummel 1957; Stevens 1967a; Martin 1981).
Although considerable information is available about the biology
of ES cells (Robertson 1987; Hogan et al. 1994), much less is
known about susceptibility to spontaneous testicular germ cell tu-
mors. TGCTs originate during critical transitions in the develop-
ment of primordial germ cells (PGCs), the embryonic precursors of
the germline. These tumors are composed of a disorganized col-
lection of various cell and tissue types derived from all three
primary germ layers and at various stages of differentiation
(Stevens 1967b). In humans, 96% of tumors in the testis are tes-
ticular germ cell tumors (Buetow 1995; Bosl and Motzer 1997).
Genetic factors influence susceptibility to testicular cancer in both
humans and mice (Stevens 1967a; Forman et al. 1992; Heimdal et
al. 1997; Bishop et al. 1998; Matin et al. 1999; Rapley et al., 2000),
but the identity of these genes has remained elusive. The 129/Sv
inbred strain is an outstanding model to study inherited suscepti-
bility to TGCTs, as well as development of the germline. In this
review, we summarize the current understanding of the biology of
TGCTs in mice, recent progress toward dissecting the genetic and
molecular control of TGCT susceptibility, and the relevance of
these studies to germline development in mammals and testicular
cancer in humans.
Biology of TGCTs. Testicular germ cell tumors arise spontane-
ously with an incidence of 1–10% in 3-week-old 129/Sv males
(Stevens and Hummel 1957). The composition of these tumors
changes during development (Stevens 1967a). In fetal and new-
born mice, TGCTs are composed primarily of undifferentiated
embryonal carcinoma (EC) cells; in mice that are about 5 days of
age, tumors contain both undifferentiated and differentiated cell
types; and in most adult mice, tumors are completely differentiated
and lack EC cells (Fig. 1). The composition of differentiated
TGCTs is highly variable. Some contain little more than neuronal
tissues, while others contain a variety of cell and tissues types such
as neuroepithelium, bone with marrow, cartilage, teeth, muscle,
skin with hair and sebaceous glands, and glandular epithelia. These
cells and tissues are derived from all three germ layers.
The remarkably variable composition of these tumors strongly
suggests that EC cells are pluripotent. In vivo cloning experiments
provide direct evidence for this hypothesis (Kleinsmith and Pierce
1964). Single EC cells transplanted into ectopic sites in adult 129/
Sv mice differentiate into diverse cell and tissue types. In each
mouse, differentiation can be biased towards particular cell and
tissue types, depending presumably on unique cellular and envi-
ronmental factors at the transplantation site.
L.C. Stevens used a series of genital ridge grafting experiments
to identify the developmental stage at which TGCTs originate and
the cell of origin for TGCTs (Stevens 1967b). Located along the
midline in the lumbar region, the genital ridges are the primordium
of embryonic gonads into which PGCs migrate at E11. Genital
ridges from embryonic day 11 (E11) to E13 wild-type fetuses that
were grafted into adult 129/Sv mice develop into TGCTs. The
ability of a ridge to form TGCTs peaks in grafts from E11 to E12.5
fetuses and decreases in grafts from fetuses after E12.5 (Stevens
1966). Therefore, the onset of tumorigenesis probably occurs be-
tween E11 and E12.5. The essential nature of PGCs in tumorigen-
esis was demonstrated in experiments with genital ridge grafts
from E12 fetuses homozygous for the Steel mutation (Sl/Sl), which
are devoid of PGCs and which failed to develop into tumors when
grafted into 129/Sv mice (Stevens 1967b).
An important question is whether PGCs in 129/Sv mice are
pluripotent when TGCTs are initiated or whether pluripotency is
an acquired property after PGCs are transformed to EC cells. As
the only lineage that passes from generation to generation, the
developmental potential of the PGC lineage is tightly regulated.
Fertilized eggs are totipotent; early in development the germline is
set aside, and development is restricted to gametes; at fertilization,
totipotency is restored. Studies with aggregation chimeras suggest
that PGCs from E10.5 embryos are already restricted to germline
development (Donovan 1994). In TGCT-prone mice, PGCs may
not be restricted to germline development until later developmen-
tal stages, so that at the onset of tumorigenesis PGCs remain
pluripotent. Alternatively, PGCs may regain pluripotency under
certain conditions and be transformed into EC cells at E11–E12.5,
the critical period in tumorigenesis.
Correspondence to: J.H. Nadeau; E-mail: firstname.lastname@example.org
© Springer-Verlag New York Inc. 2001Mammalian Genome 12, 89–94 (2001).