Speert Debra B, Konkle Anne T M, Zup Susan L, Schwarz Jaclyn M, Shiroor Chaitanya, Taylor Michael E, McCarthy Margaret M
Department of Physiology and Program in Neuroscience, University of Maryland, Baltimore, Baltimore, Maryland 21201, USA.
Endocrinology. 2007 Jul;148(7):3391-401. doi: 10.1210/en.2006-0845. Epub 2007 Apr 5.
Steroid-mediated sexual differentiation of the brain is a developmental process that permanently organizes the brain into a male or female phenotype. Previous studies in the rodent have examined the steroid-mediated mechanisms of male brain development. In an effort to identify molecules involved in female brain development, a high-throughput proteomics approach called PowerBlot was used to identify signaling proteins differentially regulated in the neonatal male and female rat hypothalamus during the critical period for brain sexual differentiation. Focal adhesion kinase (FAK) and paxillin, both members of the focal adhesion complex family of proteins, were significantly elevated in the newborn female compared with the male hypothalamus. Sex differences in these proteins were not detected in brain regions that are not subject to substantial organizational effects of steroids. Estrogens, the aromatized products of testosterone in the male, can both masculinize and defeminize the male brain. Daily estradiol administration to neonatal females significantly reduced FAK and paxillin in the hypothalamus, and aromatase inhibition increased paxillin in males to levels comparable with females. Androgens also appear to modulate paxillin levels in combination with estrogen action. Across development, hypothalamic levels of FAK were significantly elevated in females compared with males on postnatal d 6. Synaptic circuits in the hypothalamus develop sex differences perinatally. Estradiol treatment of cultured hypothalamic neurons significantly enhanced axon branching (P<0.01), consistent with the phenotype of FAK-deficient neurons. Together, these data implicate FAK and paxillin as regulators of sex differences in neuronal morphology.
类固醇介导的大脑性别分化是一个发育过程，它将大脑永久性地组织成雄性或雌性表型。以往对啮齿动物的研究已经考察了类固醇介导的雄性大脑发育机制。为了确定参与雌性大脑发育的分子，一种名为PowerBlot的高通量蛋白质组学方法被用于识别在大脑性别分化关键期新生雄性和雌性大鼠下丘脑差异调节的信号蛋白。粘着斑激酶（FAK）和桩蛋白，这两种粘着斑复合体家族蛋白质的成员，在新生雌性大鼠下丘脑中的表达显著高于雄性。在不受类固醇显著组织效应影响的脑区未检测到这些蛋白质的性别差异。雌激素是雄性体内睾酮的芳香化产物，它既能使雄性大脑雄性化，也能使其雌性化特征消失。给新生雌性大鼠每日注射雌二醇可显著降低其下丘脑中的FAK和桩蛋白水平，而芳香化酶抑制则可使雄性大鼠的桩蛋白水平升高至与雌性相当的水平。雄激素似乎也与雌激素协同作用调节桩蛋白水平。在整个发育过程中，出生后第6天雌性大鼠下丘脑FAK水平显著高于雄性。下丘脑的突触回路在围产期出现性别差异。用雌二醇处理培养的下丘脑神经元可显著增强轴突分支（P<0.01），这与FAK缺陷神经元的表型一致。这些数据共同表明，FAK和桩蛋白是神经元形态性别差异的调节因子。
