Steroid receptor coactivator-1 (SRC-1) mediates the development of sex-specific brain morphology and behavior

Abstract

Steroid hormone action during brain development exerts profound effects on reproductive physiology and behavior that last into adulthood. A variety of in vitro studies indicate that steroid receptors require nuclear receptor coactivators for efficient transcriptional activity. To determine the functional significance of the nuclear receptor coactivator SRC-1 in developing brain, we investigated the consequence of reducing SRC-1 protein during sexual differentiation of the brain. We report that reducing SRC-1 protein interferes with the defeminizing actions of estrogen in neonatal rat brain. Our data indicate that SRC-1 protein expression is critically involved in the hormone-dependent development of normal male reproductive behavior and brain morphology.

Figure 1

SRC-1 antisense ODNs reduce SDN volume. Androgenized female rats (PN13) infused neonatally with SRC-1 antisense ODNs (AS ODN) had significantly smaller SDN volume contrasted with scrambled ODN controls (Scram ODN). The numbers in the bars represent the total number of rats per group. *, P < 0.05; t test.

Figure 2

SRC-1 antisense ODNs block behavioral defeminization of rat brain. Lordosis quotients and lordosis ratings of neonatally oil-treated male (Male), androgen-treated female (Female + TP), and oil-treated female (Females + Oil) rats hypothalamically infused with SRC-1 antisense ODNs (AS ODN), scrambled ODNs (Scram ODN), or saline vehicle control (Veh). The numbers in the bars represent total number of rats per group. Male and androgenized female rats infused neonatally with SRC-1 AS ODNs displayed higher levels of lordosis contrasted to Scram ODN or Veh control males or androgenized females (*, P < 0.05, ANOVA).

Figure 3

SRC-1 antisense ODNs do not block behavioral masculinization of rat brain. Total number of mounts from either neonatally oil-treated male (Male) or androgen-treated female (Female + TP) rats hypothalamically infused with SRC-1 antisense ODNs (AS ODN), scrambled ODNs (Scram ODN), or saline vehicle control (Veh).

Figure 4

SRC-1 antisense ODN significantly reduces SRC-1 protein in hypothalamic tissue. (Upper) Photomicrograph showing a reduction of SRC-1 protein at 160 kDa by SRC-1 antisense ODNs (AS) contrasted to scrambled ODNs (Scram). (Lower) Histogram of data collected from film analysis expressed as arbitrary gray-scale units. *, P < 0.05; t test.