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.

Deletion of Bax eliminates sex differences in the mouse forebrain

“…A small subset of AVPV neurons is dopaminergic, as identified by the presence of TH, the rate-limiting enzyme for catecholamine synthesis, and absence of dopamine-␤-hydroxylase, the enzyme required for conversion of dopamine to norepinephrine (6). In confirmation of previous reports (25,28), the number of TH-ir neurons in AVPV was much greater in female mice than in males (P Ͻ 0.0005; Fig. 3B).…”

“…Although sex differences in overall neuron number in the BNSTp have not yet been reported for mice, the cluster of androgen receptor-expressing neurons is larger in male mice than in females (27). In AVPV, overall cell density is greater in female mice than in males (5,25) and, as in rats, female mice possess about three times as many dopaminergic neurons in AVPV as do males (28). We reasoned that if Bax is essential for cell death in the BNSTp and AVPV, then sex differences in neuron number might be reduced or eliminated in Bax knockout mice.…”

“…Thus, many neural areas depend on Bax for cell death, and in those cells in which Bax is involved the requirement is profound. Gonadal steroid hormones can regulate the expression of Bax and other Bcl-2 family proteins (20)(21)(22)(23)(24)(25), suggesting a mechanism for sexually dimorphic cell death. Nonetheless, sexually dimorphic brain areas have not been examined in Bax knockout mice.…”

Sexual dimorphism in environmental epigenetic programming

“…The ratio of antiapoptotic proteins to proapoptotic proteins plays a key role in determining whether a cell survives or undergoes apoptosis [11][12][13]. In specific brain areas, testicular hormones decrease cell death during perinatal development.…”

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…These differences may be due to a differential balance in the expression of members of the antiapoptotic family of Bcl-2 genes, and those in the pro-apoptotic family of Bax family genes. Male and female mice with mutations to these genes have significant changes in neuron numbers in the AVPV and SDN-POA, and there are natural sex differences in the expression of apoptotic genes in wildtype animals [172,53,157]. More specifically, deletion of Bax (proapoptotic) abolished sex differences in AVPV cell numbers [53], and overexpression of Bcl-2 (anti-apoptotic) had a similar effect [172].…”