Direct Regulation of Adult Brain Function by the Male-Specific Factor SRY

Abstract

The central dogma of mammalian brain sexual differentiation has contended that sex steroids of gonadal origin organize the neural circuits of the developing brain. Recent evidence has begun to challenge this idea and has suggested that, independent of the masculinizing effects of gonadal secretions, XY and XX brain cells have different patterns of gene expression that influence their differentiation and function. We have previously shown that specific differences in gene expression exist between male and female developing brains and that these differences precede the influences of gonadal hormones. Here we demonstrate that the Y chromosome-linked, male-determining gene Sry is specifically expressed in the substantia nigra of the adult male rodent in tyrosine hydroxylase-expressing neurons. Furthermore, using antisense oligodeoxynucleotides, we show that Sry downregulation in the substantia nigra causes a statistically significant decrease in tyrosine hydroxylase expression with no overall effect on neuronal numbers and that this decrease leads to motor deficits in male rats. Our studies suggest that Sry directly affects the biochemical properties of the dopaminergic neurons of the nigrostriatal system and the specific motor behaviors they control. These results demonstrate a direct male-specific effect on the brain by a gene encoded only in the male genome, without any mediation by gonadal hormones.

The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

“…In the control groups, total cell counts throughout the SNc confirmed previous observations Dewing et al, 2006) that adult male rats possess significantly more TH-IR neurons than females, by approximately 15%, and the present data reveal that this was due to increased numbers in the male at levels A (open histograms, Figure 2a vs 2b). Prenatal GC treatment significantly increased the total number of TH-IR cells in the SNc in both sexes (po0.05), and analysis at each level showed that this was due primarily to a significant effect at level B and D in males, whereas in females this effect was seen at all levels ( Figure 2a and b, hatched histograms).…”

“…In the adult rat SNc estimates of TH-IR cell numbers include 3500 (Anden et al, 1966), 7300 (Hedreen and Chalmers, 1972), and 10 500 (German and Manaye, 1993). Where sex has been taken into consideration, the adult male rat SNc contains significantly more DA neurons (approximately 11 500) than the female nucleus (approximately 9000) (Dewing et al, 2006). Our values of 73967184 (males) and 66377243 (females) closely approximate the average of the published estimates and confirm a maledominant sex difference.…”

“…However, it was recently demonstrated that specific expression of the Sry gene in DA neurons of the SNc is responsible for the larger population of TH-IR cells in the male nucleus (Dewing et al, 2006). Additionally, our own studies (McArthur et al, 2006b) failed to demonstrate a role for SSHs in maintaining the maledominant sex difference in numbers of DA neurons in the adult SNc.…”

A genetically female brain is required for a regular reproductive cycle in chicken brain chimeras

“…Midbrain dopamine neurons show sexual dimorphism in rodents, and this is controlled directly by the SRY gene 16,17 . In naturally occurring gynandromorphic finches, the neural song circuit in the right hemisphere has a more masculine phenotype than that in the left hemisphere, despite the influence of steroid hormones, which should be identical on both sides 18 .…”

A diferenciação do cérebro masculino e feminino

“…Esse gene se expressa especificamente nos neurônios que expressam a enzima tirosina hidroxilase da substância negra cerebral. Em estudo experimental com ratos machos, a supressão do SRY resulta em déficit motor, embora o número de neurônios permaneça o mesmo 4 , o que sugere o envolvimento desse gene em importantes propriedades bioquímicas dos neurônios dopaminérgicos do sistema nigroestrial no sexo masculino. As células cerebrais da mulher e do homem apresentam diferenças nos padrões de expressão de outros genes que são específicos para o cérebro em desenvolvimento, os quais determinam funções e habilidades específicas para cada gênero 1 .…”