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Molecular and Cellular Biology, September 2003, p. 6702-6712, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6702-6712.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Disruption of the Inosine 5'-Monophosphate Dehydrogenase Type I Gene in Mice

Jing Jin Gu,1 Amy K. Tolin,1,2,{dagger} Jugnu Jain,3 Hai Huang,1,{ddagger} Lalaine Santiago,1 and Beverly S. Mitchell1,2,4,5*

Lineberger Comprehensive Cancer Center,1 Curriculum in Genetics and Molecular Biology,2 Department of Medicine,4 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina,5 Cell Biology and Immunology, Vertex Pharmaceuticals Inc., Cambridge, Massachusetts3

Received 4 March 2003/ Returned for modification 10 April 2003/ Accepted 16 June 2003

Inosine 5'-monophosphate dehydrogenase (IMPDH) is the critical, rate-limiting enzyme in the de novo biosynthesis pathway for guanine nucleotides. Two separate isoenzymes, designated IMPDH types I and II, contribute to IMPDH activity. An additional pathway salvages guanine through the activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) to supply the cell with guanine nucleotides. In order to better understand the relative contributions of IMPDH types I and II and HPRT to normal biological function, a mouse deficient in IMPDH type I was generated by standard gene-targeting techniques and bred to mice deficient in HPRT or heterozygous for IMPDH type II. T-cell activation in response to anti-CD3 plus anti-CD28 antibodies was significantly impaired in both single- and double-knockout mice, whereas a more general inhibition of proliferation in response to other T- and B-cell mitogens was observed only in mice deficient in both enzymes. In addition, IMPDH type I-/- HPRT-/0 splenocytes showed reduced interleukin-4 production and impaired cytolytic activity after antibody activation, indicating an important role for guanine salvage in supplementing the de novo synthesis of guanine nucleotides. We conclude that both IMPDH and HPRT activities contribute to normal T-lymphocyte activation and function.

* Corresponding author. Mailing address: 22-044 LCCC, CB#7295, University of North Carolina, Chapel Hill, NC 27599. Phone: (919) 966-5720. Fax: (919) 966-8212. E-mail: mitchell{at}med.unc.edu.

{dagger} Present address: TransTech Pharma, High Point, NC 27265.

{ddagger} Present address: Center for Demographic Studies, Duke University, Durham, N.C.

Molecular and Cellular Biology, September 2003, p. 6702-6712, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6702-6712.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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