Journal of Genetics and Genomics

An everlasting role of animal models in understanding human disease

Yang Xiao, Yang Chonglin

2010, 37(9) doi: 10.1016/S1673-8527(09)60075-8

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Now and future of mouse mutagenesis for human disease models

Yoichi Gondo

2010, 37(9): 559-572. doi: 10.1016/S1673-8527(09)60076-X

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One of the major objectives of the Human Genome Project is to understand the biological function of the gene and genome as well as to develop clinical applications for human diseases. For this purpose, the experimental validations and preclinical trails by using animal models are indispensable. The mouse (Mus musculus) is one of the best animal models because genetics is well established in the mouse and embryonic manipulation technologies are also well developed. Large-scale mouse mutagenesis projects have been conducted to develop various mouse models since 1997. Originally, the phenotype-driven mutagenesis with N-ethyl-N-nitrosourea (ENU) has been the major efforts internationally then knockout/conditional mouse projects and gene-driven mutagenesis have been following. At the beginning, simple monogenic traits in the experimental condition have been elucidated. Then, more complex traits with variety of environmental interactions and gene-to-gene interactions (epistasis) have been challenged with mutant mice. In addition, chromosomal substitution strains and collaborative cross strains are also available to elucidate the complex traits in the mouse. Altogether, mouse models with mutagenesis and various laboratory strains will accelerate the studies of functional genomics in the mouse as well as in human.

The Notch signaling pathway in retinal dysplasia and retina vascular homeostasis

Minhua Zheng, Zifeng Zhang, Xingcheng Zhao, Yuqiang Ding, Hua Han

2010, 37(9): 573-582. doi: 10.1016/S1673-8527(09)60077-1

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The retina is one of the most essential elements of vision pathway in vertebrate. The dysplasia of retina cause congenital blindness or vision disability in individuals, and the misbalance in adult retinal vascular homeostasis leads to neovascularization-associated diseases in adults, such as diabetic retinopathy or age-related macular degeneration. Many developmental signaling pathways are involved in the process of retinal development and vascular homeostasis. Among them, Notch signaling pathway has long been studied, and Notch signaling-interfered mouse models show both neural retina dysplasia and vascular abnormality. In this review, we discuss the roles of Notch signaling in the maintenance of retinal progenitor cells, specification of retinal neurons and glial cells, and the sustaining of retina vascular homeostasis, especially from the aspects of conditional knockout mouse models. The potential of Notch signal manipulation may provide a powerful cell fate- and neovascularization-controlling tool that could have important applications in treatment of retinal diseases.

TGF-β signaling in aortic aneurysm: another round of controversy

Fuyu Lin, Xiao Yang

2010, 37(9): 583-591. doi: 10.1016/S1673-8527(09)60078-3

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Aortic aneurysm (AA) is a common health problem with high mortality and no effective drugs. Transforming growth factor-β (TGF-β) superfamily members regulate various cellular processes, and TGF-β signaling has key roles in development, tissue homeostasis, and diseases. Interest in the role of TGF-β signaling in the pathogenesis of AAs has recently emerged, particularly since genetic studies demonstrated an association between gene mutations in components of TGF-β signaling and AAs. However, paradoxical discoveries have implicated dysregulated TGF-β signaling in aneurysm formation, complicating the precise functional role for TGF-β in aneurysm development and progression. Furthermore, interventions targeting towards TGF-β signaling using losartan, which may represent a suitable therapeutic option for AAs, were subject to skepticism especially because of conflicting experimental results obtained from TGF-β antibody treatment without knowledge of the underlying mechanism. We propose a TGF-β aneurysm paradox, which would provide a good opportunity for the development of genetic mouse models of AA. These models would be used to clarify the mechanisms underlying TGF-β signaling, which would translate into novel pharmacologic therapies based on the new molecular discoveries.

Wg signaling in Drosophila heart development as a pioneering model

Xiushan Wu

2010, 37(9): 593-603. doi: 10.1016/S1673-8527(09)60079-5

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The heart is one of the first functional embryonic organs occurring during development. The fundamental developmental processes and genes involved in cardiogenesis are conserved between the invertebrates and vertebrates. In the past fifteen years, one of signaling pathways that has been best characterized in heart development in both invertebrates and vertebrates is the Wg/Wnt signaling pathways. Since our discovery of the Wg signaling required for the early heart development inDrosophila, the past fifteen years have witnessed tremendous progress in the understanding of specific Wnt signaling pathways in vertebrate cardiogenesis. This review will summarize the current state of knowledge of Wg signaling transduction in Drosophila heart development, which will benefit our understanding of vertebrate cardiogenesis and human congenital malformations.

POSH is involved in Eiger-Basket (TNF-JNK) signaling and embryogenesis in Drosophila

Ming Zhang, Yongqing Zhang, Zhiheng Xu

2010, 37(9): 605-619. doi: 10.1016/S1673-8527(09)60080-1

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TNFα can trigger different signaling pathways, including the JNK pathway, to regulate various biological functions such as cell death, differentiation and proliferation. The scaffold protein POSH (Plenty of SH3 Domains) has been shown to be an important regulator of the JNK pathway, but whether it is involved in TNF-signaling has not been reported. Although POSH has been implicated to play a role in development in zebrafish, it has not been studied in null mutants and the underlying mechanism of its effects is still not clear. In this study, we provide evidence that the JNK pathway scaffold protein, POSH, is involved in TNF (Eiger) signaling in Drosophila. POSH is likely to act downstream of dTAB2 and upstream of dTAK1 in the TNF-JNK signaling pathway. In addition, we found that POSH is essential during Drosophila embryogenesis, including epidermal dorsal closure, similar to other JNK pathway components such as Silpper, Hemipterous, and Basket. We observed defects in F-actin accumulation and adherens junction formation during dorsal closure in different posh null mutants, suggesting that POSH is required for epidermal cell migration and cell-shape change during epidermal dorsal closure.

A small scale expression screen identifies tissue specific markers in the Dugesia japonica strain Pek-1

Changxin Ma, Xiaoan Wang, Shuizhou Yu, Guoliang Chai, Hanxia Su, Liang Zheng, Wei Wu

2010, 37(9): 621-635. doi: 10.1016/S1673-8527(09)60081-3

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Freshwater planaria has tremendous capacity to reform the missing part of the body and therefore is considered as one of the most important model organism for regeneration study. At present,Schmidtea mediterranea and Dugesia japonica are the two major species utilized for laboratory manipulations. Dugesia japonica flatworms are widely distributed in the Far East including Cherry Valley region in the north-west area of Beijing, China. We reported here the establishment of an asexual Dugesia japonica strain Pek-1, as a suitable system for regeneration study. Using morphological, karyotypical as well as phylogenetic analyses, we confirmed that these flatworms indeed belonged to Dugesia japonica. We went on to show that the commonly used in situ probes and immunohistochemistry reagents and protocols were applicable to the Pek-1 strain. Using this strain, we carried out small scale analysis on EST, RNAi and gene expression. We identified 193 unique EST sequences and 65 of them had not been reported in planarian. By RNAi analysis, we showed that 48 genes, when down-regulated individually, had no effect on regeneration. Furthermore, we identified 3 groups of tissue specific expressing genes that were useful for cell lineage analysis. We concluded that the Dugesia japonica Pek-1 strain could be another suitable animal model to regeneration research.

Embryonic expression and evolutionary analysis of the amphioxus Dickkopf and Kremen family genes

Yujun Zhang, Bingyu Mao

2010, 37(9): 637-645. doi: 10.1016/S1673-8527(09)60082-5

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The secreted Wnt signaling inhibitor Dickkopf1 (Dkk1) plays key role in vertebrate head induction. Its receptor Kremen synergizes with Dkk1 in Wnt inhibition. Here we have carried out expression and functional studies of the Dkk and Kremen genes in amphioxus (Branchiostoma belcheri). During embryonic and larval development, BbDkk1/2/4 is expressed in the posterior mesoendoderm, anterior somatic mesoderm and the pharyngeal regions. Its expression becomes restricted to the pharyngeal region on the left side at larval stages. In 45 h larvae, BbDkk1/2/4 is expressed specifically in the cerebral vesicle. BbDkk3 was only detected at larval stages in the mid-intestine region. Seven Kremen related genes were identified in the genome of the Florida amphioxus (Branchiostoma floridae), clustered in 4 scaffolds, and are designated Kremen1-4 and Kremen-like 1-3, respectively. In B. belcheri, Kremen1 is strongly expressed in the mesoendoderm during early development and Kremen3 is expressed asymmetrically in spots in the larval pharyngeal region. In luciferase reporter assays, BbDkk1/2/4 can strongly inhibit Wnt signaling, while BbDkk3, BbKremen1 and BbKremen3 can not. No co-operative effect was observed between amphioxus Dkk1/2/4 and Kremens, suggesting that the interaction between Dkk and Kremen likely originated later during evolution.

Atp4b promoter directs the expression of Cre recombinase in gastric parietal cells of transgenic mice

Zengming Zhao, Ning Hou, Yanxun Sun, Yan Teng, Xiao Yang

2010, 37(9): 647-652. doi: 10.1016/S1673-8527(09)60083-7

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Parietal cells are one of the largest epithelium cells of the mucous membrane of the stomach that secrete hydrochloric acid. To study the function of gastric parietal cells during gastric epithelium homeostasis, we generated a transgenic mouse line, namely, Atp4b-Cre, in which the expression of Cre recombinase was controlled by a 1.0 kb promoter of mouse (-subunit of H⁺-, K⁺-ATPase gene (Atp4b). In order to test the tissue distribution and excision activity of Cre recombinase in vivo, the Atp4b-Cre transgenic mice were bred with the reporter strainROSA26 and a mouse strain that carries Smad4 conditional alleles (). Multiple-tissue PCR of mice revealed that the recombination only happened in the stomach. As indicated by LacZ staining, ROSA26;Atp4b-Cre double transgenic mice showed efficient expression of Cre recombinase within the gastric parietal cells. These results showed that this Atp4b-Cre mouse line could be used as a powerful tool to achieve conditional gene knockout in gastric parietal cells.

2010 Vol. 37, No. 9