Estrogen and androgen differentially modulate the growth-associated protein GAP-43 (neuromodulin) messenger...

The level of expression of the gene encoding GAP-43, a protein implicated in neurite outgrowth and motility, is sexually dimorphic in the postnatal brain and modulated by testosterone (T). To determine which metabolite of T modulates the expression of GAP-43 in the postnatal brain, the present study investigated the effect of estrogen and androgen receptor antagonists, tamoxifen (TAM) and cyproterone acetate (CA), and agonists, diethylstilbestrol (DES) and dihydrotestosterone (DHT). On postnatal day 1, male rats were injected sc daily with oil, TAM, or CA, whereas additional female pups were treated with oil, DES, or DHT. On postnatal day 6, brains were collected and 16-micron cryostat sections processed and hybridized with a 35S-labeled antisense riboprobe complementary to GAP-43 messenger RNA (mRNA). A comparison of hybridization signal in the cerebral cortex, bed nucleus of the stria terminalis, and medial preoptic nucleus demonstrated that the level of GAP-43 mRNA in males was significantly higher than in females. However, when male pups were injected with CA, a female-like level of GAP-43 mRNA was measured in the cerebral cortex. The low level of GAP-43 hybridization signal in the female cortex was markedly increased when females were treated with DHT. In contrast, the level of GAP-43 mRNA in the male medial preoptic nucleus was attenuated after treatment with TAM, whereas the level in the female was augmented with DES. Interestingly, the level of GAP-43 mRNA in the bed nucleus was reduced when males were treated with either TAM or CA and augmented when females were administered either DES or DHT. The results of these studies indicate that the effects of T on GAP-43 mRNA levels in the postnatal brain are modulated by estrogen- and androgen receptor-mediated events in a region-specific manner.