Neural androgen receptor overexpression affects cell number in the spinal nucleus of the bulbocavernosus

Abstract

The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic neuromuscular system in which the masculinisation of cell number is assumed to depend on the action of perinatal androgen in non-neural targets, whereas the masculinisation of cell size is assumed to depend primarily on the action of adult androgen on SNB cells themselves. To test these hypotheses, we characterised the SNB of Cre/loxP transgenic mice that overexpress androgen receptor (AR) throughout the body (CMV-AR) or in neural tissue only (Nestin-AR). Additionally, we examined the effects of androgen manipulation in male mutants and wild-type (WT) controls. We reproduced the expected sex differences in both motoneurone number and size, as well as the expected adult androgen dependence of SNB size. We found effects of genotype such that both Nestin-AR and CMV-AR have more SNB motoneurones than WT littermates and also that CMV-AR females have larger SNB motoneurones than Nes-AR or WT females. These results raise the possibility that AR can act in neurones and/or glia to rescue SNB motoneurones, as well as on non-neural AR to increase SNB cell size.

Both neural and global androgen receptor overexpression affect sexual dimorphism in the mouse brain

“…In rodent brain, sex differences in neural morphology appears to result from both signalling pathways. Although purely oestrogenic or purely androgenic actions of testosterone on sexual differentiation of brain are uncommon, sexual differentiation of motoneurones comprising the spinal nucleus of the bulbocavernosus (SNB) appears to rely almost exclusively on androgenic signalling …”

“…In addition to the complexity of mixed signalling pathways for testosterone, there is uncertainty as to where in the body testosterone acts to cause sex differences. There is growing appreciation of the importance of interactions between peripheral structures and the central nervous system in the process of sexual differentiation and we have very little knowledge about the site of testosterone action in producing sex differences in the rodent brain. In the SNB, testing for direct and indirect actions of androgens has proved feasible, leading to the discovery of multiple sites of androgen action with respect to producing various sexually dimorphic features in these neurones .…”

“…There is growing appreciation of the importance of interactions between peripheral structures and the central nervous system in the process of sexual differentiation and we have very little knowledge about the site of testosterone action in producing sex differences in the rodent brain. In the SNB, testing for direct and indirect actions of androgens has proved feasible, leading to the discovery of multiple sites of androgen action with respect to producing various sexually dimorphic features in these neurones . Much of the work underlying these conclusions used loss of function mutations of AR, including Tfm and conditional ARKO animals, which largely lead to understanding whether AR is necessary.…”

“…Much of the work underlying these conclusions used loss of function mutations of AR, including Tfm and conditional ARKO animals, which largely lead to understanding whether AR is necessary. To complement this knowledge, we have examined the effects of global or nervous system‐specific overexpression of AR on the SNB system, as well as the effects of selective overexpression of AR in target muscles on sexual differentiation and androgen response of motoneurones . Overexpression studies allow us (a) to understand the extent to which increased AR is sufficient to produce known effects of testosterone and (b) to produce complementary effects to those resulting from loss of AR function.…”

“…To parse the neural and non‐neural effects of AR on brain sex differences, we used the same mouse models of selective (neural or global) AR overexpression . This transgenic mouse model comprises of Cre/loxP‐driven AR overexpression in which AR was induced selectively in neural tissue (Nestin‐cre) or in all tissues (CMV‐cre).…”