Deletion of Bax eliminates sex differences in the mouse forebrain

Abstract

Several of the best-studied sex differences in the mammalian brain are ascribed to the hormonal control of cell death. This conclusion is based primarily on correlations between pyknotic cell counts in development and counts of mature neurons in adulthood; the molecular mechanisms of hormone-regulated, sexually dimorphic cell death are unknown. We asked whether Bax, a member of the Bcl-2 family of proteins that is required for cell death in many developing neurons, might be essential for sex differences in neuron number. We compared Bax knockout mice and their WT siblings, focusing on two regions of the mouse forebrain that show opposite patterns of sexual differentiation: the principal nucleus of the bed nucleus of the stria terminalis, in which males have more neurons than do females, and the anteroventral periventricular nucleus (AVPV), where females have more neurons overall and many more dopaminergic neurons than do males. Testosterone, or its metabolites, is responsible for the sex differences in both nuclei. A null mutation of the Bax gene completely eliminated sex differences in overall cell number in both the principal nucleus of the bed nucleus of the stria terminalis and AVPV. Thus, Bax-dependent cell death is required for sexual differentiation of cell number, regardless of whether testosterone decreases or increases cell death. In contrast, the sex difference in AVPV dopaminergic cell number, as measured by tyrosine hydroxylase immunohistochemistry, was not affected by Bax gene deletion, demonstrating heterogeneity of mechanisms controlling cell number within a single nucleus.

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].…”

Hypothalamic control of the male neonatal testosterone surge

“…Another interesting aspect of this proposed pathway is that it effectively results in male neonatal RP3V kisspeptin neurons sealing their own demise through a 'kiss of death'. The neonatal testosterone surge drives programmed cell death [31] to generate the sexual dimorphic features of the RP3V. Thus, in generating the testosterone surge, the neonatal RP3V kisspeptin neurons initiate a sequence of events that leads to their own demise as potential kisspeptin neurons are killed in the male to generate the 10-fold female-dominant number of kisspeptin neurons within the RP3V [61,78].…”