Dominant negative effects of HNF-1β mutation on the development of MODYS in transgenic mouse models

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Hepatocyte nuclear factor-1α (HNF-1α) and HNF-1β are transcriptional activator proteins and belong to the same homeoprotein family. The mutations of these genes are responsible for maturity onset diabetes of the young 3 (MODY3) and MODY5, respectively. HNF-1α and HNF-1β can form homo- or hetro-dimer and bind to the same target DNA sequences in vitro. On the other hand, a decrease of HNF-1α expression in mouse caused glucose intolerance but a decrease of HNF-1β expression in mouse did not. So, we hypothesize that the dominant negative effect of HNF-1β but not HNF-1α mutation is crucial for development of MODY. In this study, we aim to make a transgenic mouse that over-expresses a dominant-negative HNF-1β mutant protein and try to elucidate the mechanism for the develomnent of MODY5. In the term of this project, we made some vectors by which the dominant-negative HNF-1β mutant protein could be expressed and injected these vectors to some fertilized mouse eggs. Unfortunately, however, we can not get any positive transgenic mouse until now. The reason is that the vectors would not be suitable for the expression in mouse, or that the expression of the mutant protein would have some toxic effects on the development of mouse embryo. Now we are checking about these possibilities. In relation to the vector, we recently succeed to make a transgenic mouse that over-expresses a kind of amino acid transporter in β cell specifically. So we plan to change the mutant HNF-1β cDNA to this vector which we used for the injection to express the amino acid transporter.