Begin at the beginning and go on till you come to the end; then stop. - Lewis Carroll

There is a rather comprehensive review of developmental events leading to sex differences in gonads, genitalia, and brain in the current Nature Reviews Genetics. I think one of the most interesting things that becomes apparent as you delve into this literature is that maleness in the brain can be attributed to three (if not more) dissociable factors: Testosterone, Sry (the O.G. sex determining gene), and other unspecified genes on the Y chromosome. To some extent these factors depend on each other, but it is possible to manipulate one experimentally and get behavioral/brain effects without affecting the others.

Sry is the gene on the Y chromosome that says to make testes instead of ovaries. There is only one highly-conserved domain in the SRY protein, and effing with it causes serious problems in sexual development. The structure of this domain suggests that SRY should be interacting with DNA (probably regulating the levels of other genes), but there is still no clear direct downstream target. Somewhere further downstream a gene called Sox9 plays an important role. A recent discussion in PLOS Biology (free!) lays out the story to-date. Sry leads to more Sox9, which in turn leads to more Fgf9. Fgf9 and Sox9 interact in a positive feedback loop to produce sustained high levels necessary for differentiation of Sertoli cells. Sertoli cells are one of the first male-specific cell-types to differentiate. They provide a comfortable niche for production of healthy happy sperm, and probably secrete factors to tell other cells to become other important male-specific cell-types.

This may be a good time to remind everyone what these genes do at the cellular level. Sox9 is a transcription factor. Transcription factors interact directly with the DNA and alter the production of other downstream genes. They often do this by either directly helping to recruit the transcription machinery or by recruiting chromatin modifying factors. Chromatin consists of the proteins (like histones) that DNA is all wrapped up in and around. Chromatin modification can loosen or tighten the DNA-protein interaction and make the DNA more or less available for transcription. Fgf9 is a growth factor (fibroblast growth factor 9, to be exact). Growth factors are generally secreted and bind to extracellular surface receptors. When growth factors bind to receptors they often induce an intracellular signaling cascade. The receptor itself is a signaling molecule that can modify proteins downstream and activate or deactivate them. Oftentimes a transcription factor will sit somewhere downstream in the growth factor receptor's signaling cascade, so growth factors can indirectly affect transcription.

You need all of that Sry, Sox9, Fgf9 business to get gonads and start making testosterone which has a major impact on the developing and adult brain. However, people are beginning to discover gonad-independent effects of Sry. A report in the February 2006 issue of Current Biology showed that SRY is expressed in the substantia nigra of the adult male mouse brain and seems to directly affect dopamine production. The substantia nigra is one of two major dopamine producing centers in the brain (the other being the ventral tegmental area). The report showed that specifically knocking down SRY on one side of the substantia nigra turned down the production of tyrosine hydroxylase (TH). TH is the rate-limiting step in dopamine production. Animals with SRY reductions showed motor deficits on the opposite side of the body from the depletion. Female TH levels and motor performance were unaffected by the SRY treatment (since they didn't ever have any SRY to knockdown), indicating that dopamine production is differentially regulated in males and females.

All this talk of dopamine and motor deficits got me thinking about Parkinson's. It seems that there is a 3:2 male-to-female ratio in PD diagnosis. People have been investigating the protective effects of certain female-specific hormones, but this genomic difference may also help explain some of the difference in susceptibility. As far as cognition goes, I'm afraid this doesn't help us out much. There are some hints that the substantia nigra plays a role in reward learning, but the VTA is the dopamine center that has been tied to higher cognitive function.

A day after the Current Biology paper came out, the Journal of Neuroscience had a paper out that separates the behavioral effects of Sry-mediated gonad generation from the rest of the Y chromosome. In a previous work, this group produced mice that had Sry deleted from the Y chromosome and inserted on an autosome. This allows you to have XY female mice and XX male mice (male and female here refer to gonadal sex). Presence of the Y chromsome minus Sry influenced aggression and parental behavior in the same direction that male gonads did. Also, the Y chromosome affected the amount of vasopressin in the lateral septum (associated with parenting and social behavior in rodents). So genes on the Y chromosome besides the major testes-determining factor help push the brain into maleness in a direction complementary to the effects of testosterone. There is a little speculation as to which genes these might be, but not much. This could still be a matter of higher gene dosage of some X-linked gene in XX over XY mice.

Sex differences in the brain begin before the testes are formed and thus happen outside the influence of testosterone. Testosterone plays a huge role, but the Y chromosome and particularly Sry do more than specify gonads. It may be that there is no essence of man, but that man is made up of components that can be varied independently. These gonad-chromosome mash-ups are extreme, but may be mirrored by more subtle variations in the naturally occurring population. Testosterone can enhance verbal, spatial, and working memory and increase aggression, but the aggression effect of chromosomal maleness persists in the absence of a male hormonal environment. I cannot readily pin a cognitive attribute on SRY effects in the brain, but the fact that it specifically affects dopamine in the substantia nigra suggests that it's affects will be circumscribed and independent of the gonads and the rest of the Y chromosome.