Current Genomics - Volume 2, Issue 1, 2001

The mouse has long been an important component of cancer research. From the realization by Little and Bagg early days of the past century demonstrating a heritable component of sponanteous cancer to the oncogenic manipulations of the germline today, the mouse has been and will continue to be the major mammalian in vivo system to study neoplasic transformation and progression. Use of the mouse has pervaded almost every aspect of cancer research, including discovery of oncogenes, analysis of tumor suppressors, development of novel therapeutic strategies, and exploring the mutagenic effects of chemicals and ionizing radiation, to name a few. The development over the last twenty years of transgenic, homologous recombination and conditional-transgenic or knockout technologies has enormously expanded the breadth and scope of the mouse in cancer research and has contributed significantly to our understanding of the events that lead up to and accompany neoplastic transformation. Although there are significant limitations of modeling human cancers in the mouse, these proven technologies as well as technologies currently under development, will continue to provide experimentally tractable systems in which to explore the genetic and molecular events of cancer initiation and progression. As a result, the mouse as a model for human neoplastic disease will continue to have a significant place in the experimental toolbox of cancer researchers for many years to come.

Knowing the mutational basis of a disease does not always explain the mechanism of pathogenesis, particularly when little is known about the disease-associated proteins themselves. This is very likely to be an ever-growing problem in the genomics era. The polyglutamine (polyQ) repeat disorders are an intriguing example of such a scientific dilemma. These human diseases presently include the spinocerebellar ataxia type 1 (SCA1, SCA2, SCA3, SCA6, SCA7), Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), and dentatorubropallidoluysian atrophy (DRPLA) (1). With the exception of SBMA and SCA6, due to the expansion of a polyQ in the androgen receptor and alpha1A voltage-dependent calcium channel, respectively, the wild-type function of the gene products are not understood. While the cloning of the polyQ genes has provided important genetic information, the biochemical mechanism responsible for each was not readily apparent.To gain insight into the molecular basis of polyQ-induced pathogenesis, investigators have turned to the development and characterization of disease models. Transgenic mice, in combination with cell culture models, have proven to be very useful tools for elucidating factors important for polyQ pathogenesis. This review focuses on those polyQ diseases for which informative studies have been undertaken using transgenic mice. For each disease, relevant information gleaned from other experimental approaches is also incorporated into the discussion.

A search for susceptibility genes for psychiatric illness may benefit from recent advances in mouse molecular genetics. Molecular and phenotypic characterization of single gene mutations in mice with anomalies in neurophysiological or neurodevelopmental processes, disrupted in a psychiatric disease, can reveal new insights into the pathways that underlie these genetically complex illnesses. However, in the case of many psychiatric disorders such as autism and schizophrenia, the exact nature of these neurophysiological or neurodevelopmental processes is not known. For example, nothing is known about the molecular pathology underlying impaired social behavior, a prominent feature of both autism and schizophrenia. In this review we discuss published reports on genetic and pharmacological studies of social behavior in mice. We argue that paradigms for studies of the genetics and neurobiological origins of social interactions in mice are amenable to gene- and phenotype-based mutagenesis screens and that identification of a core set of genes that underlie social behavior in mice may provide important clues for our understanding of some aspects of autism and schizophrenia.

Impairment of hearing is the most common sensory deficit in human populations. Most cases of human deafness are hereditary. Mutations in many different genes can affect the complex process of hearing. The mouse is an excellent model for studies of these hearing disorders because the anatomy, function, and hereditary abnormalities of the ear have been shown to be similar in both humans and mice. More than 100 spontaneous, chemically-induced, and genetically engineered mouse mutations have been discovered with hearing impairment many of these provide valuable models for both non-syndromic and syndromic forms of human deafness. So far, a total of 64 loci for human non-syndromic hearing impairment have been mapped, the genes responsible for 20 have been identified, and mouse models are available for 8 of these genes. More than 400 human syndromes have been described with associated hearing impairment, and about 80 genes have been identified. Mutations of homologous genes in the mouse have provided models for many of these syndromes. Studies of human hearing disorders and their mouse counterparts have contributed much to our understanding of the hearing process. For example, they have identified molecules (unconventional myosins, espins, and cadherins) that are important for the proper organization of hair cell stereocilia, ion transport and gap junction proteins that regulate endocochlear ion concentrations, and extracellular matrix proteins that compose acellular membranes important in auditory transduction. Genetically diverse inbred strains of mice provide models of age-related and noise-induced hearing loss and also provide a means to discover modifier genes by assessing mutant phenotypes on different strain backgrounds. With the new human and mouse genome initiatives now underway, the mouse will become an even more important animal model for hearing research.

Epilepsies are defined as a group of disorders with recurrent seizures. It is now well-established from human studies that a good proportion of these epilepsies are inherited. The same finding is true for mice as there are several examples of mouse models showing monogenic and multigenic inheritance of epilepsy. This article reviews the recent developments in mouse positional cloning leading to the identification of many epilepsy-related genes in monogenic absence and convulsive seizure models of the mouse. Surprisingly, four of the six known absence seizure mouse models have mutations in the voltage-dependent calcium channel subunit genes. In contrast, mice with spontaneous single gene and targeted gene disruptions causing convulsive seizures reveal an assortment of genes, including those encoding ion channels, transcription factors, myelin and vesicle proteins. For the more complex seizure models with multiple gene defects, quantitative trait loci have been identified but the underlying genes have yet to be found. The challenges of fine-mapping and locating the genes for these traits are also discussed.