Figure 2. Sex chromosomes affect brain development directly and indirectly.

The differentiation of the bipotential gonad into a testis versus an ovary depends on the SRY gene, which is located on the Y chromosome. If present, the gonad will become a testis, and, if not, it will become an ovary¹⁸. Testosterone and its aromatized end product oestradiol produced by the embryonic testis bind to their cognate receptors, which regulate gene transcription and exert an organizing influence on cells in the developing brain. Ovarian and testicular steroids also activate sex-specific physiology and behaviour in adulthood. Moreover, every cell in the brain is XY in male mammals and XX in female mammals. Genes on the X chromosome may be expressed at different levels in males and females (in cases in which they escape from X inactivation in females)¹¹³, whereas genes on the Y chromosome (such asSRY) are expressed only in the brain of males²⁰. In females, the presence of a second X chromosome could create a heterochromatic sink by monopolizing the cellular machinery used for epigenetic regulation and thus alter the expression of other genes in a manner that is distinct from males. Thus, the sex chromosomes can exert both specific and broad influences on the developing brain. ER, oestrogen receptor.