Expanding our Understanding of Polyglutamine Disease Through Transgenic Mice Pp. 27-39
Jennifer D. Davidson and Harry T. Orr
Social Behavior as an Endophenotype for Psychiatric Disorders: Development of Mouse Models Pp. 41-54
Dubravka Hranilovic and Maja Bucan
Mouse
Models of Human Hearing Disorders. Pp. 55-69
Kenneth R. Johnson
[Back to top] The Mouse In Cancer Research; Past, Present,
Future(?).
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.
[Back to top] Expanding our Understanding of Polyglutamine Disease Through Transgenic Mice.
Knowing the mutational basis of a disease does not always explain themechanism of pathogenesis, particularly when little is known about the disease-associatedproteins 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..
[Back to top] Social Behavior as an Endophenotype for Psychiatric Disorders: Development of Mouse Models
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 neuro
developmental 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
[Back to top] Mouse
Models of Human Hearing Disorders.
Kenneth R. Johnson
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.