TfM mutation and masculinization versus feminization of the mouse central nervous system

The sexual behavior of mice of various genotypes has been studied in our stock in which X-linked genes, Tfm and (O^hv), as well as an autosomal dominant gene, Sxr, are maintained. Since the absence of neonatal imprinting in Tfm (O^hv)/Y^ leads to no sexual behavior, we conclude that neonatal imprinting is the prerequisite for feminization as well as masculinization of the central nervous system. Since individual components of sexual behavior may become feminine or absent instead of being masculine in sex-reversed Tfm (O^hv)/+(O⁺, Sxr/+^♂ with mosaic brains, we conclude that neonatal imprinting directly involves individual neurons, and that different degrees of imprinting by the same agent lead to masculinization or feminization. In accordance with recent views, we believe estradiol to be this imprinting agent.We envisage the role of the Tfm locus in the central nervous system as follows: within individual neurons for sexual behavior, the synthesis of aromatizing enzymes is normally inducible by androgens; these enzymes are therefore noninducible in Tfm (O^hv)/Y^. In normal neonates, exposure to testosterone leads to the induced intracellular conversion of testosterone to estradiol, self imprinting by estradiol causing masculinization. Feminization may normally be due to the direct exposure of these neurons to a low circulating concentration of estradiol. An alternative explanation might be that the estradiol-receptor protein in these neurons also is normally inducible by testosterone. In this case, neonatally testosterone-exposed neurons would become inherently more responsive to estradiol than neonatally estradiol-exposed neurons.