New solutions to an ancient riddle: defining the differences between Adam and Eve.

As our current knowledge of the mammalian sex-differentiation pathway expands, a connection of this process to the potential genetic regulation of sexual behavior and sex-specific development of the brain is natural. At least in invertebrate systems, a tangible genetic link has been forged between the sex-development pathway and normal courtship behavior. Two genes, fruitless and dissatisfaction, are now known to contribute to normal male courtship behavior, by specifying the identity of neurons required for execution of the reproductive behaviors. Additionally, these genes begin to define new branches of the Drosophila sex-determination pathway that are downstream of the transformer gene (tra) and apparently independent of one another (Finley et al. 1998xDissatisfaction encodes a tailless-like nuclear receptor expressed in a subset of CNS neurons controlling Drosophila sexual behavior. Finley, KD, Edeen, PT, Foss, M, Gross, E, Ghbeish, N, Palmer, RH, Taylor, BJ et al. Neuron. 1998; 21: 1363–1374Abstract | Full Text | Full Text PDF | PubMed | Scopus (70)See all References1998, and references therein). These findings offer an interesting new perspective for those contemplating the potential mechanisms governing sex differences in the mammalian brain.Previous studies have shown that steroids affect sex-specific brain development during critical periods before and after birth, with consequences for adult behavior (for review, see Breedlove 1992xSexual dimorphism in the vertebrate nervous system. Breedlove, SM. J Neurosci. 1992; 12: 4133–4142PubMedSee all References1992). For instance, perinatal exposure of female animals to sex steroids can masculinize adult behaviors, and androgens can alter the morphology of brain nuclei, such as in the case of the sexually dimorphic nucleus of the preoptic area of the hypothalamus. Defining the precise contributions of individual nuclei to adult sexual behavior has been difficult. Moreover, the effects of sex steroids on brain development are complex, because these steroids are locally metabolized, as in the case of androgens. One major metabolite of the aromatization of testosterone is estrogen, which is generally assumed to be required in male-specific brain development. The persistence of a masculine preoptic area in androgen-insensitive rats suggests that some developmental effects of testosterone occur after aromatization to estrogen (Breedlove 1992xSexual dimorphism in the vertebrate nervous system. Breedlove, SM. J Neurosci. 1992; 12: 4133–4142PubMedSee all References1992). Interestingly, deficiency for the estrogen-receptor subtype ERα in mice disrupts male-specific aggressive and mating behaviors but does not affect male sexual motivation (Ogawa et al. 1997xBehavioral effects of estrogen receptor gene disruption in male mice. Ogawa, S, Lubahn, DB, Korach, KS, and Pfaff, DW. Proc Natl Acad Sci USA. 1997; 94: 1476–1481Crossref | PubMed | Scopus (314)See all References1997). Moreover, male mice lacking aromatase are fully capable of breeding (Fisher et al. 1998xCharacterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Fisher, CR, Graves, KH, Parlow, AF, and Simpson, ER. Proc Natl Acad Sci USA. 1998; 95: 6965–6970Crossref | PubMed | Scopus (629)See all References1998). These recent studies underscore how little is understood regarding the molecular basis of sex steroids and their cognate nuclear receptors, in brain development and sex differences in the brain.Continued molecular and genetic investigations will be required to identify which steroids and what nuclei or brain regions are involved in sexually dimorphic brain development. These studies promise to be challenging, given the complexity of (a) steroid action on early brain development and modulation of adult behavior and (b) the indirect effects of steroid action on peripheral tissues. It will be of great interest to know whether mammals use a steroid-independent arm of the sex-determination cascade to dictate sex differences in the brain, as Drosophila does. During the next decade, the convergence of vertebrate genetics, behavior analyses, and genomics should elucidate the remaining mysteries of gonadal development and may begin to provide a genetic rationale for neurological and behavioral differences between men and women.