Association between susceptibility to Theiler's virus-induced demyelination and T-cell receptor Jbeta1-Cbeta1 polymorphism rather than Vbeta deletion.

Theiler's murine encephalomyelitis virus (TMEV) induces demyelinating disease in susceptible mouse strains after intracerebral inoculation. The clinical symptoms and histopathology of the central nervous system appear to be similar to those of human multiple sclerosis (MS), and thus, this system provides an excellent infectious animal model for studying MS. The virus-induced demyelination is immune mediated, and the genes involved in the immune response such as those for the T-cell receptor beta-chain and major histocompatibility complex (MHC) haplotypes are known to influence disease susceptibility. To define whether the T-cell receptor Jbeta-Cbeta or Vbeta genes are associated with susceptibility, we have analyzed F2 mice from crosses of susceptible SJL/J (Vbeta(a)-JCbeta(b)) mice and resistant C57L (Vbeta(a)-JCbeta(a)) mice. Our results indicate that susceptibility to TMEV-induced demyelination is associated with restriction fragment length polymorphism reflecting the T-cell receptor Jbeta1-Cbeta1 region rather than the Vbeta polymorphism. This association becomes stronger when the MHC haplotype is considered in the linkage analysis. However, differences in the T-cell receptor alpha-chain haplotype have no significant influence on the pathogenesis of TMEV-induced demyelination.

Functional inactivation but not structural mutation of p53 causes liver cancer.

Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.

Evolving concepts in molecular pathology.

During the last decade, an understanding of the causes of many human diseases has progressed rapidly, in large measure because of the development of technologies that allow us to identify the genes that are involved. Identification of a gene that is suspected to play an important role in a particular disease opens up a whole new dimension of research to understand the molecular events that underlie the cause of that disorder. A crucial step in this process is often the development of an animal model of the disease. Again, the last decade has seen rapid advances in our ability to create such models, particularly in mice. Technologies that allow for the addition, alteration, or elimination of individual genes from the genome to create a transgenic mouse are now routine. The advantages of having a transgenic mouse model of a human disease are many. These animals often provide the first unequivocal proof that a particular gene is responsible for causing the pathological changes that occur with disease. They also can provide a system to carefully dissect the successive events that lead to the disease state, and can provide a custom-designed whole animal system to test potential therapies to treat and eventually cure the disease. Most important, new concepts relating to gene expression and gene function in disease often emerge from such transgenic studies. This review will illustrate several examples in which transgenic animals have contributed significantly to the evolution of concepts of the underlying mechanisms of human disease.

Regulating gene expression in transgenic animals.

Regardless of the field of application, the raison d'etre of transgenic animals is to study gene regulation and function. With increasing frequency, mammalian genes are being isolated with no concomitant knowledge of their function. The human genome mapping initiative will undoubtedly produce a cornucopia of such genes. While the merit of taking a transgenic route to study genes of unknown function is axiomatic, the choices of strategies for gene regulation in vivo may not be fully appreciated. This review will address two main points: first, the targeted and regulated expression of genes, and second, the structural and functional ablation of genes.

Hierarchy of effects of the MHC and T cell receptor beta-chain genes in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Intracerebral inoculation of susceptible mice with Theiler's murine encephalomyelitis virus induces a demyelinating disease that is similar to human multiple sclerosis. This murine model for human multiple sclerosis is apparently immune-mediated and the genes involved in the immune response influence the outcome of disease susceptibility as observed with human multiple sclerosis. These genes include the MHC and TCR genes. However, the functional relationships among these genes on the disease susceptibility has not yet been studied. In this study, we demonstrate that the effect of the H-2s genotype from susceptible SJL/J mice overrides the resistant effect of the BALB/c TCR beta-chain gene in CXJ recombinant-inbred and BALB.S congenic mice. These results strongly suggest the presence of a hierarchy of genes involved in the immune response in Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Influence of sex on susceptibility in the Theiler's murine encephalomyelitis virus model for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease in humans which affects females more frequently than males. Theiler's murine encephalomyelitis virus (TMEV) induces demyelination similar to human MS in susceptible strains of mice after intracerebral inoculation. In this paper we report that sex influences susceptibility to TMEV-induced demyelination in certain genotypes derived from C57L/J and SJL/J or SWR/J mice. This is the first report of an animal model for MS that shows an association between sex and susceptibility, and this information may facilitate the investigation of human MS.

Reduction of rat pineal N-acetyltransferase activity by fetal alcohol exposure.

Pineal N-acetyltransferase (NAT) is activated by increased sympathetic activity or by administration of isoproterenol. These experiments examined the effects of fetal alcohol exposure on the pharmacological induction of NAT activity in rats. Fetal alcohol exposure resulted in a significant reduction of NAT activity compared to that in rats whose mothers received a nutritionally controlled liquid diet or a laboratory chow diet during gestation. Stimulation of NAT activity in vitro by forskolin, which directly stimulates adenylate cyclase, also was significantly less in pineal glands from fetal alcohol exposed rats when compared with pineal NAT activity from rats exposed to the control diets during gestation. The results suggest that the effects of fetal alcohol exposure is not limited to the beta-adrenergic receptor at the cell membrane, but that exposure to alcohol in utero may result in more general effects on intracellular mechanisms involved in pineal NAT enzyme synthesis or activity.

Postnatal or in utero ethanol exposure reduction of the volume of the sexually dimorphic nucleus of the preoptic area in male rats.

Adult male rats exposed to alcohol in utero results in reduction of the volume of the sexually dimorphic nucleus of the preoptic area (SND-POA). Reduction of the volume of this nucleus is also significantly reduced in rats exposed to ethanol postnatally compared to the volume in animals not exposed to ethanol (P less than 0.05). The results indicate that ethanol exposure during the postnatal period of brain development in rats is equally effective as in utero ethanol exposure in development of the SDN-POA volume. This report substantiates others demonstrating the deleterious effects of ethanol consumption during the 'critical' period of brain development.