Direct regulation of adult brain function by the male-specific factor SRY.
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.
Department of Human Genetics, University of California, Los Angeles, Los Angles, California 90095, USA.
Phoebe
P
Dewing
Charleston W K
CW
Chiang
Kevin
K
Sinchak
Helena
H
Sim
Pierre-Olivier
PO
Fernagut
Sabine
S
Kelly
Marie-Francoise
MF
Chesselet
Paul E
PE
Micevych
Kenneth H
KH
Albrecht
Vincent R
VR
Harley
Eric
E
Vilain
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D024282:Genes, sry / Q000502:physiology*; D008297:Male; D051379:Mice; D009043:Motor Activity; D017072:Neostriatum / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D012727:Sex Characteristics; D013378:Substantia Nigra / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine