How can research in a simple invertebrate illuminate the mechanisms that shape sex differences in the vertebrate nervous system? Though C. elegans has a strong history of defining conserved genetic mechanisms critical for neural development and function, the mechanisms used by vertebrates to effect sexual differentiation of the nervous system seem, at first glance, fundamentally different from those in C. elegans. As described above, gonadal hormones have long been considered to be the sole arbiter of these processes in vertebrates; their effects, particularly in mammals, are both powerful and well demonstrated. In contrast, steroid hormones have no obvious role in the sex-specific development of the C. elegans nervous system, though whether they regulate sex-specific behavior in the worm is an open question. However, the C. elegans genome contains no obvious orthologues of the androgen or estrogen receptors so that vertebrate gonadal steroids are unlikely to be involved.
A revision of this orthodox view has come from a series of recent studies in vertebrates that have demonstrated that cell-autonomous sex determination pathways, acting in parallel to gonadal hormones, function in the nervous system to link sexual karyotype to the development of sex-specific characteristics. Arnold has proposed that regulatory genes on the X (that escape dosage compensation) and Y chromosomes may directly organize sex-specific CNS characteristics (Arnold, 2004). Indeed, there is some evidence that the Y-chromosome sex-determining gene Sry has such a role in the nervous system (Dewing et al., 2006). However, such a model may capture only one aspect of this process. It is also quite possible that sexual karyotype controls much more complex regulatory networks, such as those characteristic of C. elegans and Drosophila sex determination, that read the sex-determining signal and set into motion a cascade of interactions that only very indirectly lead to sex-specific gene expression. The potential existence of such a pathway in the mammalian nervous system has intriguing implications for the mechanisms that bring about sex differences in neuroanatomy and neural function; moreover, genes in such a pathway could have central importance in the development of a wide variety of neurological and mental heath conditions, such as autism, mental retardation, and anxiety disorders, that occur with strong sex bias in humans. As conserved regulators of sexual fate with critical functions in C. elegans sexual dimorphism, DM-domain factors could be important components of such a mechanism. Further genetic analysis of sex differences in C. elegans neural development and behavior is likely to lead to additional candidates regulating similar processes in much more complicated, less experimentally tractable organisms.
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