Elsevier

Physiology & Behavior

Volume 73, Issue 5, August 2001, Pages 859-871
Physiology & Behavior

Murine models for Down syndrome

https://doi.org/10.1016/S0031-9384(01)00523-6Get rights and content

Abstract

The availability of the recently published DNA sequence of human chromosome 21 (HSA21) is a landmark contribution that will have an immediate impact on the study of the role of specific genes to Down syndrome (DS). Trisomy 21 or DS is the only autosomal aneuploidy that is not lethal in the fetal or early postnatal period. DS phenotypes show variable penetrance, affecting many different organs, including brain (mental retardation, early onset of Alzheimer's disease, AD), muscle (hypotonia), skeleton, and blood. DS phenotypes may stem directly from the cumulative effect of overexpression of specific HSA21 gene products or indirectly through the interaction of these gene products with the whole genome, transcriptome, or proteome. Mouse genetic models have played an important role in the elucidation of the contribution of specific genes to the DS phenotype. To date, the strategies used for modeling DS in mice have been three: (1) to assess single-gene contributions to DS phenotype, using transgenic techniques to create models overexpressing single or combinations of genes, (2) to assess the effects of overexpressing large foreign DNA pieces, introduced on yeast artificial chromosomes (YACs) or bacterial artificial chromosomes (BACs) into transgenic mice, and (3) mouse trisomies that carry all or part of MMU16, which has regions of conserved homology with HSA21. Here we review the existing murine models and the relevance of their contribution to DS research.

Introduction

Trisomy of human chromosome 21 (HSA21) produces a variety of developmental anomalies recognized as Down syndrome (DS). The disorder affects one in about 700 newborns and is the most significant genetic cause of mild to moderate mental retardation, due to alterations in neural development. Individuals with trisomy 21 may show several abnormalities to various extents, including craniofacial dysmorphology, short stature, congenital defects of the heart and gastrointestinal tract, infertility (mostly in men), immune system alterations, thyroid dysfunction, or hematopoietic disorders that include a higher incidence of childhood leukemias. At a gross morphological level, DS brains are smaller than normal, brain weight is reduced disproportionately, mostly affecting the cerebellum and brainstem, and the depth and number of sulci are reduced. Neuronal number is reduced in distinct regions, including the cochlear nuclei, cerebellum, hippocampus, the cholinergic neurons of the basal forebrain, the granular layers of the cerebral cortex and areas of the brain stem, and abnormal neuronal morphology is observed, especially in the cerebral cortex. In addition, over the age of 35, DS individuals exhibit neuropathological alterations typical of Alzheimer's disease (AD) and frequently show premature aging (see [23], [26], [73] for review). There are many other disorders involving HSA21 genes, such as familial amyotrophic lateral sclerosis, familial AD, Ewing's sarcoma, and other primitive neuroectodermal tumors and acute myeloid leukemia.

Defining how an extra copy of all or part of HSA21 results in the phenotype of DS is a specific case of the more general problem of explaining how chromosomal imbalance produces abnormalities in morphology and function. No single mechanism can explain the deleterious consequences of aneuploidy, and therefore, there is no simple solution to counteract its phenotypic impact. While some loci may have a greater phenotypic effect, it is the cumulative effect of imbalance of many genes that determines the overall phenotypes. Two hypothesis have been proposed to explain DS phenotype: (i) the amplified developmental instability hypothesis [84] suggests that the DS phenotype is the result of a nonspecific disturbance of chromosome balance, resulting in a disruption of homeostasis; (ii) in contrast, the gene dosage hypothesis proposes that DS phenotypes may stem directly from the cumulative effect of overexpression of specific chromosome 21 gene products or indirectly through the interaction of these HSA21 genes products with the whole genome, transcriptome, or proteome. Evidence from different murine models points to specific genes affecting phenotypes rather than the unspecific effect of the amount of extra genetic material (see Ref. [72] for review). However, we still cannot answer the question of how three copies of normal genes contribute to the abnormal phenotype of DS.

Based on the analysis of human individuals with segmental trisomy 21, it has been proposed that genetic loci situated in the DS critical region (DSCR) could harbor genes with major effect. However, the resolution of this approach is limited by the high phenotypic variation among DS individuals and to date no convincing evidence exists of the association between any particular phenotypic trait and overexpression of a specific HSA21 gene. The availability of the recently published DNA sequence of HSA21 [40] will have an immediate impact on the study of the genetic aspects of DS by providing a comprehensive catalogue of the genes on HSA21. However, the functions of most of these genes remain largely unknown, as does their contribution, if any, to the DS phenotype. Even knowing the molecular defect, it is difficult to decipher the complex pathophysiology of the disease, the developmental consequences of the trisomy, and the impact on behavior and cognitive function. Thus, we are now facing a new era, the postgenomics in which the goal will be to identify protein function and physiological role of gene products. The generation of animal models is a powerful tool to help us to understand the role of individual genes in DS and some of its clinical alterations, and it provides ready access to cells and tissues from different developmental stages of the disease. However, it should be borne in mind that DS is a complex disorder caused by an extra copy of a whole set of genes. Due to the fact that some genes are highly regulated, the impact of gene overdosage on the transcription level may vary. The presence of three copies of many of these genes may result either in different degrees of overexpression or repression of few transcripts and can be even more dramatic at the protein expression level. In addition, they can interact with each other and/or affect expression of genes located on other chromosomes.

Various approaches have been used to study the consequences of increased gene dosage in DS and to investigate phenotype/genotype relationships of HSA21 genes in mice [53] (Fig. 1): (1) transgenic animals overexpressing single or combinations of genes, (2) transgenic mice with large foreign DNA pieces introduced on yeast artificial chromosomes (YACs) or bacterial artificial chromosomes (BACs), and (3) mouse models that carry all or part of MMU16, which has regions of conserved synteny with HSA21.

Section snippets

The use of transgenesis for modeling DS

The use of transgenic techniques to model human disease has led to major advances in our understanding of pathogenic mechanisms, but has also highlighted the limitations of conventional transgenic methodology for the production of accurate animal models, and the difficulties associated with modeling human pathophysiology in mice. Important issues are the use of the same genetic background [30], but also a good phenotypic characterization, based on standardized protocols [14], [78]. Attempts are

YAC/BAC/PAC transgenics

In many cases, the knowledge of the sequence of a particular gene requires intensive effort and thus cannot be applied efficiently to the generation of transgenic models. The development of YAC/BAC/PAC technology for the generation of transgenic mice holds enormous potential for studying aneuploidy syndromes such as DS. It is possible to transfer large pieces of DNA that may encompass several genes, thus allowing the study of the effects of multiple genes as opposed to single-gene effects. YACs

Mouse trisomies

Orthologous genes are frequently linked in similarly conserved chromosomal segments in the mouse and human genomes (Mouse Genome Database: http://www.informatics.jax.org). For this reason aneuploidy for regions of the mouse genome that are conserved on human chromosomes can serve to study the concerted effect of over- (or under-) expression of multiple genes. HSA21 shows conserved syntenies to mouse chromosomes 16, 17, and 10 [40]. Comparative mapping between mice and humans has revealed that

Acknowledgements

This work was supported in part by grants of CEC/BIOMED2 (BMH4-CT98-3039), CICYT (SAF99-0092-CO2-01), FIS 00/0795, and Fundación Marcelino Botı́n.

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