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Molecular and Cellular Biology, February 2003, p. 923-932, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.923-932.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Liver-Specific Reactivation of the Inactivated Hnf-1 Gene: Elimination of Liver Dysfunction To Establish a Mouse MODY3 Model

Ying-Hue Lee,^1,* Mark A. Magnuson,² Vijayakumar Muppala,¹ and Shih-Shun Chen^1,3

Laboratory of Molecular Pathology, Institute of Molecular Biology, Academia Sinica, Taipei 115,¹ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 100, Taiwan,² Departments of Molecular Physiology and Biophysics and of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37233³

Received 13 May 2002/ Returned for modification 9 August 2002/ Accepted 21 October 2002

Mice deficient in hepatocyte nuclear factor 1 (HNF-1) develop dwarfism, liver dysfunction, and type 2 diabetes mellitus. Liver dysfunction in HNF-1-null mice includes severe hepatic glycogen accumulation and dyslipidemia. The liver dysfunction may appear as soon as 2 weeks after birth. Since the HNF-1-null mice become diabetic 2 weeks after birth, the early onset of the liver dysfunction is unlikely to be due to the diabetic status of the mice. More likely, it is due directly to the deficiency of HNF-1 in liver. Although the HNF-1-null mice have an average life span of 1 year, the severe liver phenotype has thwarted attempts to study the pathogenesis of maturity-onset diabetes of the young type 3 (MODY3) and to examine therapeutic strategies for diabetes prevention and treatment in these mice. To circumvent this problem, we have generated a new Hnf-1 mutant mouse line, Hnf-1^kin/kin, using gene targeting to inactivate the Hnf-1 gene and at the same time, to incorporate the Cre-loxP DNA recombination system into the locus for later revival of the Hnf-1 gene in tissues by tissue-specifically expressed Cre recombinase. The Hnf-1^kin/kin mice in which the expression of HNF-1 was inactivated in germ line cells were indistinguishable from the HNF-1-null mice with regard to both the diabetes and liver phenotypes. Intriguingly, when the inactivated Hnf-1 gene was revived in liver (hepatic Hnf-1 revived) by the Cre recombinase driven by an albumin promoter, the Hnf-1^kin/kin mice, although severely diabetic, grew normally and did not develop any of the liver dysfunctions. In addition, we showed that the expression of numerous genes in pancreas, including a marker gene for pancreas injury, was affected by liver dysfunction but not by the deficiency of HNF-1 in pancreas. Thus, our hepatic-Hnf-1-revived mice may serve as a useful mouse model to study the human MODY3 disorder.

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* Corresponding author. Mailing address: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan. Phone and fax: 886-2-26517983. E-mail: mbying{at}ccvax.sinica.edu.tw.

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Molecular and Cellular Biology, February 2003, p. 923-932, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.923-932.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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