Highest ADA Expressing Mouse Tissues Also Exhibit Cell-Type Specific Coordinate Up-Regulation of Purine Degradative Enzymes

Abstract

During previous studies of human ADA gene regulatory elements in transgenic mice (Aronow et al. 1989) we noted the profound degree of up-regulation of the endogenous mouse ADA gene in both the post-natal gastrointestinal tract (Lee 1973, Chinsky et al. 1990), and the post-implantation reproductive tract (Knudsen et al. 1988). ADA specific activity and mRNA levels in these tissues exceeds those observed in thymus, which is thought to be the principle site of biochemical pathology in ADA deficient humans. Within the proximal GI tract, there are also some striking tissue specific species differences between humans and mice. For example, humans do express ADA at high levels in the duodenum and thymus, but do not in most other tissues including tongue and esophagus (Aronow et al. 1989). In mice, ADA expression occurs in a somewhat similar pattern but very high-level expression also occurs in tongue, esophagus, forestomach. High level ADA expression has not been observed in human placenta, but the placentas of rat, cat, cow, guinea pig, and rabbit have been reported to contain very high levels of ADA at some stages of gestation (Brady and O’Donovan, 1965; Sim and Maguire, 1970). To approach the question as to why ADA is expressed at high level in some of these locations, we have attempted to observe the expression of the other purine catabolic enzymes. In this study we demonstrate that the entire series of purine catabolic pathway enzymes are expressed in identical cell types and undergo developmental co-regulation throughout the proximal GI tract. We also observe a similar co-expression of purine catabolic enzymes in a distinct population of cells of the post-implantation maternal decidua long been known to express high levels of 5’NT (Hall 1971) and more recently ADA (Knudsen et al. 1988, 1991). Like the mature GI tract, a substantial subset of cells in the reproductive tract also appear committed to the degradation of purine nucleotides.