Tissue-specific Rescue Suggests That Placental Adenosine Deaminase Is Important for Fetal Development in Mice

doi:10.1074/jbc.270.41.23891

Tissue-specific Rescue Suggests That Placental Adenosine Deaminase Is Important for Fetal Development in Mice (*)

From the (1)Verna and Mars McLean Department of Biochemistry,
(2) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

** To whom correspondence should be addressed. Tel.: 713-798-4572; Fax: 713-796-9438; rkellems{at}bcm.tmc.edu

↵^¶ Current address: Merck Research Laboratories, West Point, PA 19486.

Abstract

Adenosine deaminase (ADA, EC 3.5.4.4) is an essential enzyme of purine metabolism that is expressed at very high levels in the murine placenta where it accounts for over 95% of the ADA present at the fetal gestation site. We have recently shown that ADA-deficient fetuses, which also lack ADA in their adjoining placentas, die during late fetal development in association with profound purine metabolic disturbances and hepatocellular impairment. We have now investigated the potential importance of placental ADA by genetically restoring the enzyme to placentas of ADA-deficient fetuses. This genetic engineering strategy corrected most of the purine metabolic disturbances, prevented serious fetal liver damage, and rescued the fetuses from perinatal lethality. Our findings suggest that placental ADA is important for murine fetal development and illustrate a general strategy for the tissue specific correction of phenotypes associated with null mutations in mice.

Footnotes

↵^§ Supported by National Institutes of Health Postdoctoral Fellowship HD07843.
↵* This work was supported by National Institutes of Health Grants GM42436, DK46207, and HD30302. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

ADA

adenosine deaminase

dpc

days postcoitum

HPLC

high performance liquid chromatography

AdoHcy

S-adenosylhomocysteine

kb

kilobase pair(s)

bp

base pair(s).
↵²M. R. Blackburn and S. K. Datta, unpublished observations.
↵³M. Wakamiya, unpublished observations.
- Received July 20, 1995.
- Revision received August 17, 1995.