Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord

Abstract

Several sex differences in the nervous system depend on differential cell death during development in males and females. The anti-apoptotic protein, Bcl-2, promotes the survival of many types of neurons during development and in response to injury. To determine whether Bcl-2 might similarly control cell death in sexually dimorphic regions, we compared neuron number in wild-type mice and transgenic mice overexpressing Bcl-2 under the control of a neuron-specific promoter. Three neural areas were examined: the spinal nucleus of the bulbocavernosus (SNB), in which neuron number is greater in males; the retrodorsolateral nucleus (RDLN) of the spinal cord, which exhibits no sex difference in neuron number; and the anteroventral periventricular nucleus (AVPV) of the hypothalamus, in which both overall cell density and the number of tyrosine hydroxylase immunoreactive (TH-ir) neurons are greater in females. Bcl-2 overexpression significantly increased SNB cell number in females, overall cell density of AVPV in males, and RDLN cell number in both sexes. Bcl-2 overexpression did not alter the number of TH-ir neurons in AVPV of males or females. These findings indicate that Bcl-2 can regulate sexually dimorphic cell number in the brain and spinal cord and suggest that Bcl-2 may mediate effects of testosterone on cell survival during neural development. In contrast to the regulation of overall cell density in AVPV, the sex difference in TH cell number apparently is not caused by a Bcl-2-dependent mechanism.

Fig. 1.

The mean (±SEM) number of SNB motoneurons in wild-type (WT) and Bcl-2-overexpressing (Bcl-2 OE) mice. Bcl-2 overexpression increased motoneuron number in females but not in males. n =numbers at base of bars. n.s., Not significant.

Fig. 2.

Motoneuron number in the RDLN of wild-type and Bcl-2-overexpressing mice. A, There was no sex difference in RDLN cell number. Bcl-2 overexpression increased the total number of RDLN motoneurons by ∼22%, and the increase was significant for both sexes. B, The number of RDLN motoneurons classified as small was increased by 114% in Bcl-2-overexpressing mice; this increase was significant for both males and females. n = numbers at base of bars.

Fig. 3.

Overall cell density and the number of tyrosine hydroxylase (TH)-immunoreactive neurons in AVPV.A, Overall cell density was higher in females than in males (p < 0.01). Bcl-2 overexpression significantly increased AVPV cell density in males. B, Females had 3.3 times as many TH-immunoreactive neurons in AVPV as did males (p < 0.0005). Bcl-2 overexpression had no effect on TH cell number in either sex. n =numbers at base of bars.