ISOLATION OF A NEW MOUSE 3-HYDROXYSTEROID DEHYDROGENASE ISOFORM, 3-BETA-HSD-VI, EXPRESSED DURING EARLY-PREGNANCY

The enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) is a key e nzyme in the biosynthesis of steroid hormones. To date, this laborator y has isolated and characterized five distinct 3 beta-HSD complementar y DNAs (cDNAs) in the mouse (3 beta-HSD I through V). These different forms are expressed in a tissue- and developmentally-specific manner a nd fall into two functionally distinct enzymes. 3 beta-HSD I and III, and most likely II, function as dehydrogenase/isomerases, whereas 3 be ta-HSD IV and V function as 3-ketosteroid reductases. This study descr ibes the isolation, characterization, and tissue-specific expression o f a sixth member of this gene family, 3 beta-HSD VI. This neu; isoform functions as an NAD(+)-dependent dehydrogenase/isomerase exhibiting v ery low Michaelis-Menten constant (K-m) values for pregnenolone (simil ar to 0.035 mu M) and dehydrocpiandrosterone (similar to 0.12 mu M). 3 beta-HSD VI is the earliest isoform to be expressed during embryogene sis in cells of embryonic origin at 7 and 9.5 days postcoitum (pc), an d is the major isoform expressed in uterine tissue at the time of impl antation (4.5 days pc) and continues Co be expressed in uterine tissue at 6.5, 7.5, and 9.5 days pc. 3 beta-HSD VI is expressed in giant tro phoblasts at 9.5 days pc and is expressed in the placenta through day 15.6 pc. In the adult mouse, 3 beta-HSD VI appears to be the only isof orm expressed in the skin and also is expressed in the testis, but to a lesser extent than 3 beta-HSD I. Mouse 3 beta-HSD VI cDNA is ortholo gous to human 3 beta-HSD I cDNA. Human type I 3 beta-HSD has been show n to be the only isoform expressed in the placenta and skin. The demon stration that mouse 3 beta-HSD VI functions as a dehydrogenase/isomera se and is the predominant isoform expressed during the first half of p regnancy in uterine tissue and in embryonic cells suggests that this i soform may be involved in local production of progesterone, which is n eeded for successful implantation of the blastocyst and/or maintenance of early pregnancy.