Testicular teratocarcinogenesis in mice--a review.

Spontaneous testicular germ cell tumours in humans and mice are remarkable for their diverse composition. These tumours are usually composed of an extraordinary variety of cell and tissue types including muscle, skin, bone, cartilage, and neuroepithelia. Their diverse composition reflects their origin from totipotent primordial germ cells at about Day 12 of fetal development. Although much is known about the development of these tumours, remarkably little is known about the genetics of the mammalian primordial germ cell lineage or about the genes that control susceptibility to spontaneous testicular germ cell tumours in humans or mice. Conventional genetic analysis of susceptible 129/Sv mice is difficult because of the large number of susceptibility genes and their low penetrance. We are taking advantage of the Ter mutation to simplify the genetic analysis. Various evidence suggests that Ter is neither necessary nor sufficient for tumourigenesis. Instead, Ter acts as a modifier, dramatically increasing tumour incidence from approximately 1% in +/+ males, to approximately 17% in Ter/+ males and approximately 94% in Ter/Ter males. Segregation analysis suggests that Ter increases tumour incidence by requiring some, but perhaps not all, of the 129/Sv-derived susceptibility genes. With standard crosses that segregate for the Ter mutation, identification not only of Ter but also of these 129/Sv-derived susceptibility genes should be possible. In this paper, we review the genetics and development of germ cell tumours in 129/Sv mice, summarize the status of Ter mapping, and provide evidence that different genetic pathways lead to unilateral and bilateral tumours.

Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I-dependent.

MHC class II alleles clearly contribute a primary genetic component of susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. However, IDDM does not occur in NOD mice made MHC class I-deficient by a functionally inactivated beta2-microglobulin allele (beta2m(null)). In the present study the beta2m(null) mutation was used to examine the relative contributions of MHC class I and class II-dependent T cell responses for initiating autoimmune pancreatic beta cell destruction in NOD mice. Splenocytes from diabetic NOD donors transferred IDDM to both lymphocyte-deficient NOD-scid (class I+) and NOD-scid.beta2m(null) mice (class I-). In contrast, splenocytes from young prediabetic NOD donors only transferred IDDM to class I+, but not class I- NOD-scid recipients. However, splenocytes from prediabetic NOD donors did transfer IDDM to NOD-scid.beta2m(null) recipients previously engrafted with class I+, but not class I-, pancreatic islets. CD4+ T cell lines reactive against some syngeneic class I+ targets could be isolated from NOD.beta2m(null) mice. However, NOD.beta2m(null) T cells underwent activation-driven deletion when transferred into class I+ NOD-scid recipients. Hence, the class I autoreactive T cells present in NOD.beta2m(null) donors did not elicit IDDM when transferred into class I+ NOD-scid recipients. Collectively, these results show that autoimmune IDDM in NOD mice is initiated by MHC class I-dependent T cell responses, but this leads to the subsequent activation of additional T cell populations that can mediate pancreatic beta cell destruction in a MHC class I-independent manner.

B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new "speed congenic" stock of NOD.Ig mu null mice.

The T lymphocytes mediating autoimmune destruction of pancreatic beta cells in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes mellitus (IDDM) may be generated due to functional defects in hematopoietically derived antigen-presenting cells (APC). However, it has not been clear which particular subpopulations of APC (B lymphocytes, macrophages, and dendritic cells) contribute to the development and activation of diabetogenic T cells in NOD mice. In the current study we utilized a functionally inactivated immunoglobulin (Ig) mu allele (Ig mu null) to generate a "speed congenic" stock of B lymphocyte-deficient NOD mice that are fixed for linkage markers delineating previously identified diabetes susceptibility (Idd) genes. These B lymphocyte NOD.Ig mu null mice had normal numbers of T cells but were free of overt IDDM and insulitis resistant, while the frequency of disease in the B lymphocyte intact segregants was equivalent to that of standard NOD mice in our colony. Thus, B lymphocytes play a heretofore unrecognized role that is essential for the initial development and/or activation of beta cell autoreactive T cells in NOD mice.

Genetic regulation of traits essential for spontaneous ovarian teratocarcinogenesis in strain LT/Sv mice: aberrant meiotic cell cycle, oocyte activation, and parthenogenetic development.

Strain LT/Sv female mice show a high frequency of spontaneous ovarian teratomas arising from parthenogenetically activated follicular oocytes. LT/Sv oocytes also arrest at metaphase of meiosis I, rather than progressing through to metaphase II, as do almost all fully grown oocytes from most other strains. We investigated a new set of recombinant inbred strains derived from BALB/c and C58 (the progenitor strains of LT/Sv) and crosses of these two progenitor strains and found that metaphase I arrest is necessary, but not sufficient, to cause parthenogenetic activation. Occurrence of progeny with phenotypes more extreme than either parent (transgressive variation) suggests that these traits are polygenic and that LT/Sv mice inherited a novel combination of permissive alleles from their progenitor strains. Absence of teratomas from some LT-related strains demonstrate that metaphase I arrest and parthenogenetic activation are not sufficient for teratoma formation and that additional permissive alleles are required for teratocarcinogenesis. Finally, segregation analysis of teratoma formation in these strains suggests that a single autosomal gene derived from C57BL/6J mice is responsible for the high tumor incidence in one of these strains, LTXBO. Together these results show that metaphase I arrest, parthenogenetic activation of oocytes, and teratoma formation are multigenic traits involving a modest number of permissive alleles.

Interaction between undulated and Patch leads to an extreme form of spina bifida in double-mutant mice.

The aetiology of spina bifida involves genetic and environmental factors, which may be why major genes contributing to pathogenesis have not been identified. Here we report that undulated-Patch double-mutant mice have a phenotype reminiscent of an extreme form of spina bifida occulta in humans. This unexpected phenotype in double-mutant but not single-mutant mice shows that novel congenital anomalies such as spina bifida can result from interaction between products of independently segregating loci. This example of digenic inheritance may explain the often sporadic nature of spina bifida in humans.

A mutation in the Ter gene causing increased susceptibility to testicular teratomas maps to mouse chromosome 18.

Little is known about inherited susceptibility to spontaneous germ cells tumours in humans or other species. The Ter mutation in laboratory mice is novel in that it acts codominantly to reduce germ cell numbers on many inbred strain backgrounds and to enhance dramatically inherited predisposition to spontaneous testicular teratocarcinomas in strain 129 inbred mice. We have adopted a PCR-based, DNA pooling method for mice with 'extreme' phenotypes (small testes versus normal-sized testes) to identify a candidate linkage to the Ter locus. Two independent mapping approaches confirmed this evidence for Ter linkage near D18Mit62 on mouse chromosome 18, and suggest a possible human homologue on chromosome 5q.

Two-hit model for sporadic congenital anomalies in mice with the disorganization mutation.

Congenital anomalies have complex etiologies involving both genetic and nongenetic components. Many are sporadic, without obvious evidence for heritability. An important model for these anomalies is a mutation in laboratory mice that is called "disorganization" (Ds), which functions as a variable autosomal dominant and leads to a wide variety of congenital anomalies involving many developmental processes and systems. Variable expressivity, asymmetrical manifestations, and low penetrance suggest that somatic events determine the location and nature of these anomalies. A statistical analysis suggests that occurrence of anomalies in mice with the Ds mutation follows a Poisson distribution. These results suggest that congenital anomalies in mice with the Ds mutation occur independently of each other. We propose that Ds causes a heritable predisposition to congenital anomalies and that Ds and appropriate somatic events combine to compromise normal development. We also propose that some sporadic, nonheritable congenital anomalies involve somatic mutations at Ds-like loci. Ds may therefore serve not only as a model for developmental anomalies in cell fate and pattern formation but also for complex developmental traits showing variable expressivity, low penetrance, and sporadic occurrence in mice and humans.

Disorganization is a completely dominant gain-of-function mouse mutation causing sporadic developmental defects.

Disorganization (Ds) is an exceptional mutation because of its diverse and profound developmental effects. Although other mouse mutations produce similar congenital defects, extreme pleiotropism, random occurrence, developmental independence of multiple defects, and type of anomaly make Ds unique. Examples of developmental defects include cranioschisis, rachischisis, thoracoschisis, exencephaly, hamartomas, and anomalies of appendages, digestive, genital and urinary tracts, sense organs, limbs and girdles, tail and pharynx. No other mutation in the mouse has such broad effects. Ds is therefore an important model for studying not only the genetic control of lineage determination and pattern formation, but also the occurrence of sporadic congenital defects. To characterize the effects of gene dosage, we examined the viability and phenotype of Ds homozygotes and the phenotype of +/+/Ds trisomic fetuses. Occurrence of homozygotes was tested by intercrossing Ds/+ heterozygotes, typing genetic markers that flank Ds, and examining homozygotes for morphological abnormalities. Not only were Ds homozygotes found in their expected frequency, homozygotes were not more severely affected than heterozygotes. Trisomies provide a direct test for determining whether Ds is a gain-of-function mutation. Trisomic fetuses were derived by crossing Ds/Ds homozygous mice to hybrid mice that were heterozygous for two related Robertsonian translocations. Two trisomic fetuses had developmental defects characteristic of Ds mice. Together these results demonstrate that Ds is a completely dominant, gain-of-function mutation.

Development of rib-vertebrae: a new mutation in the house mouse with accessory caudal duplications.

The new recessive mutation rib-vertebrae (rv) causes fusions of lower ribs and malformations of vertebrae, which results from disturbed somite arrangement. In addition, duplications of the caudal neural tube and sometimes unilateral suppression of kidney formation can be observed. The new mutation is compared with the six already known mutations in mice with "Wirbel-Rippen-Syndrome" and with a similar syndrome in man. From the various effects of the rv-gene observed, it is suggested that the gene causes abnormal inner and outer surface formation, producing manifold secondary effects.

Blind-sterile: a new mutation on chromosome 2 of the house mouse.

The inheritance and developmental effects of a new recessive mutation in the mouse, blind-sterile (bs), are described. This mutation causes lenticular cataracts and glossy coat in males and females and sterility in males due to arrested spermatogenesis. Blind-sterile is located on chromosome 2, near agouti.

Head blebs: a new mutation on chromosome 4 of the mouse.

The development effects and inheritance of a new mutation in the mouse, head blebs, gene symbol heb, are described. This mutation is similar to two other autosomal recessive mutations, eb and my. Head blebs produces abnormal or missing eyes due to prenatal blebs, usually on the head, some fetal death, open eyelids, and folded retinas at birth. Extra toes or ectopic brains are occasionally observed. Affected adults usually have closed eyelids and atrophic eyes. Head blebs is located on chromosome 4, four units from pintail (Pt).

Development of coloboma (Cm/+), a mutation with anterior lens adhesion.

A semidominant mutation in the laboratory mouse, Coloboma (Cm), is described. Coloboma is located on Chromosome 2, as is the similar mutation Dickie's small eye (Dey). Coloboma has a moderately reduced expressivity. The anterior chamber is usually present in Cm/+. Both Cm and Dey show delayed detachment of the lens vesicle and microphthalmia, and homozygotes of both apparently die early in pregnancy.

Development of Dickie's small eye: an early lethal mutation in the house mouse.

Mice heterozygous for Dickie's small eye (Dey) are small and have malformed eyes (Theiler et al. 1978). The development of homozygous Dey/Dey was more difficult to analyze than heterozygous Dey/+. This investigation to identify the homozygotes and to distinguish them from Dey/+ and +/+ resorptions. Such a distinction was possible only when enough specimens were available. The mutants are poor breeders and the collection of the necessary material has taken several years.

Development of Dickie's small eye, a mutation in the house mouse.

A new semidominant mutation in the laboratory mouse, Dickie's small eye (Dey), is described. It is localized on chromosome 2. Heterozygotes show reduced body size, small eyes with coloboma, small or lacking lens with cataract, abnormal folding of the retina and reduction of the pigment layer. The anterior chamber is usually missing. Homozygotes apparently die early in pregnancy.

A new allele of ocular retardation: early development and morphogenetic cell death.

The inheritance and some developmental effects of a new allele of ocular retardation (orJ) are described. Affected animals or 12 days of gestation, show reduced cell death in the eye cup and thickening of the inner wall of the optic fissure. At 11 to 13 dyas of gestation orJ/orJ eyes grafted to the testis do not produce retina as their orJ+ littermates do. Adult animals have small eyes with closed lids, abnormal retinal layers, and no optic nerve.

Malformed vertebrae: a new mutant with the "wirbel-rippen syndrom" in the mouse.

A new skeletal mutant in the house mouse, "malformed vertebrae" (MV), is described. It is semidominant. The skeletal malformations can be traced back to disturbed somite formation.