Progranulin in Sexual Differentiation of the Developing Brain

Abstract

During the perinatal period (or known as the critical period), sex-dependent differentiation of the brain occurs in response to sex steroids. Steroid hormone exposure (androgen and estrogen) can induce masculinization during the critical period, otherwise the brain develops as feminine by default. Our previous studies indicated that progranulin (PGRN) gene would be involved in masculinization of developing brain in rats. In the neonatal rat hypothalamus, administering androgen and estrogen significantly increased expression of PGRN mRNA. The level of PGRN mRNA expression remained high in males throughout the critical period of sexual differentiation in the brain; however, in females PGRN mRNA expression gradually decreased. We detected high levels of PGRN mRNA in the ventromedial hypothalamic and arcuate nuclei of the hypothalamus. Next, we designed complementary antisense oligodeoxynucleotides to the PGRN mRNA sequence and injected them into the third ventricle of newborn male rats. After sexual maturation, the treated rats displayed significantly lower scores than the controls in a variety of tests assessing copulatory behavior. Interestingly, PGRN-deficient mice also exhibited a decrease in a specific parameter of male sexual behavior. Altogether, our studies demonstrate that PGRN critically works for the organization of the neuronal system that controls male-specific functions in the developing brain.