TRANSIENT EXPRESSION OF THE 5-ALPHA-REDUCTASE TYPE-2 ISOZYME IN THE RAT-BRAIN IN LATE FETAL AND EARLY POSTNATAL LIFE

The enzyme 5 alpha-reductase plays a key role on several brain functio ns controlling the formation of anxiolytic/anesthetic steroids derived from progesterone and deoxycorticosterone, the conversion of testoste rone to dihydrotestosterone, and the removal of excess of potentially neurotoxic steroids. Two 5 alpha-reductase isoforms have been cloned: 5 alpha-reductase type 1 is widely distributed in the body, and 5 alph a-reductase type 2 is confined to androgen-dependent structures. In th is study, the gene expression of the two 5 alpha-reductase isozymes ha s been analyzed in fetal, postnatal, and adult rat brains by RT-PCR fo llowed by Southern analysis. 5 alpha-Reductase type 1 messenger RNA is always detectable in the rat brain [from gestational day 14 (GD14) to adulthood]. 5 alpha-Reductase type 2 messenger RNA expression is unde tectable on GD14, increases after GD18, peaks on postnatal day 2, then decreases gradually, becoming low in adulthood. This pattern of expre ssion appears to be correlated with the rate of production of testoste rone by the testis. The possible control by androgens of gene expressi on of the two isozymes has been studied in brain tissues of animals ex posed in utero to the androgen antagonist flutamide; the sex of the an imals was determined by genetic sex screening of the SRY gene located on the Y-chromosome. In the brain of male embryos, flutamide treatment inhibited the expression of 5 alpha-reductase type 2; this effect was much less pronounced in females. Moreover, 5 alpha-reductase type 2 g ene expression in cultured hypothalamic neurons is highly induced by t estosterone and by the phorbol ester 12-O-tetradecanoyl-phorbol-13 ace tate. The transient, androgen-regulated, expression of 5 alpha-reducta se type 2 overlaps the critical period of development, which may be im portant for sexual differentiation of the brain and for the formation of anxiolytic/anesthetic steroids involved in the stress responses ass ociated with parturition.