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For precise understanding of the mechanism for regulation of embryonic development and differentiation, it is essential to understand the mechanism for specific temporal and spatial expression of genes at the molecular level. We are identifying and analyzing genes specifically involved in the processes of embryonic development, genes involved in transduction of intra- and extracellular signals regulating differentiation, and genes involved in regulation of transcription. Furthermore, in view of the post-genomic age, we are developing new techniques capable of rapid and systematical analysis of animal gene function through experiments involving randomized gene destruction of ES cells.
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- Research on genes regulating TGF-β signals
TGF-β is dispensable for shaping of animals, e.g., for determination of the dorsoventral axis of early embryos and regulation of the differentiation of fetal skeleton. It is also involved in preservation of the function of various organs of mature organisms. Its abnormalities can lead to malignant courses of tumors and onset of common sicknesses such as pulmonary fibrosis and osteoarthritis. We have identified a previously unknown gene HtrA1 involved in the formation of bone and joint, onset of arthritis, tumor malignancy and so on, and are analyzing its physiological functions.
- Research on genes involved in the development of the nerve system
We are analyzing the action mechanisms of previously unknown genes involved in formation of nerve cells and preservation of their function. Some of these genes are responsible for human diseases such as the LRP gene involved in the onset of delayed Alzheimer disease and Atcay gene responsible for hereditary cerebellar ataxia.
- Development and application of the gene trap microarray method
In this study, two methods (“DNA microarray technique” and “randomized gene trapping with mouse ES cells”), which were previously considered as two totally different methods, are fused functionally, to yield a quite convenient technique by which when a gene showing interesting expression patterns on the microarray is detected, ES cells from which this gene has been knocked out can be obtained immediately. During the course of this study, we additionally found a hint useful in clarifying the mechanism for NMD which selectively destroys the mutant mRNA. We are advancing the study using this hint.
- Functional analysis of the genes destroyed by the gene-trap microarray technique
Using this technique, more than 1,000 genes have been destroyed, and the information obtained from them has been made public on our website. On several particularly interesting genes among these genes (e.g., Zn finger type transcription suppression factor CIBZ which regulate the development, differentiation and carcinogenesis, the gene encoding the receptor for the neurotransmitter GABA, and the Galectin gene involved in the regulation of immune responses), we have prepared knockout mice and are conducting analysis.
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- Matsuda et al., Proc. Nat. Acad. Sci. USA 101, 4170-4174, 2004
- Oka et al., Development, 131, 1041-53, 2004
- Murwantoko et al., Biochem. J. 381, 895-904, 2004
- Obata et al., Genes Cells, 6, 345-360, 2001
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Fig. 1 HtrA1 gene involved in the onset of arthritis is primarily expressed in the skeletal system of mouse fetuses and regulates the differentiation of cells in cartilage and bone.
Fig. 2 Gene-trap microarray technique. The information on the sequence of randomly knockout genes is arranged on the chip. The use of this microarray allows the patterns of gene expression to be clarified.
Fig. 3 CIBZ suppresses transcription by recruiting CtBP (a transcription suppression cofactor used commonly for various transcription suppressing mechanisms) and histone deacetylase to the heterochromatic area of the centromere.
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