Sexual Differentiation of the Spinal Nucleus of the Bulbocavernosus Is Not Mediated Solely by Androgen Receptors in Muscle Fibers

Abstract

The spinal nucleus of the bulbocavernosus (SNB) neuromuscular system is a highly conserved and well-studied model of sexual differentiation of the vertebrate nervous system. Sexual differentiation of the SNB is currently thought to be mediated by the direct action of perinatal testosterone on androgen receptors (ARs) in the bulbocavernosus/levator ani muscles, with concomitant motoneuron rescue. This model has been proposed based on surgical and pharmacological manipulations of developing rats as well as from evidence that male rats with the testicular feminization mutation (Tfm), which is a loss of function AR mutation, have a feminine SNB phenotype. We examined whether genetically replacing AR in muscle fibers is sufficient to rescue the SNB phenotype of Tfm rats. Transgenic rats in which wild-type (WT) human AR is driven by a human skeletal actin promoter (HSA-AR) were crossed with Tfm rats. Resulting male HSA-AR/Tfm rats express WT AR exclusively in muscle and nonfunctional Tfm AR in other tissues. We then examined motoneuron and muscle morphology of the SNB neuromuscular system of WT and Tfm rats with and without the HSA-AR transgene. We observed feminine levator ani muscle size and SNB motoneuron number and size in Tfm males with or without the HSA-AR transgene. These results indicate that AR expression in skeletal muscle fibers is not sufficient to rescue the male phenotype of the SNB neuromuscular system and further suggest that AR in other cell types plays a critical role in sexual differentiation of this system.

Sexual Differentiation of the Nervous System: Where the Action Is

“…This is in effect what Niel et al (1) have done by taking advantage of a simple, sexually dimorphic neuromuscular system that has been a focus of research in sexual differentiation for almost 30 years. The spinal nucleus of the bulbocavernosus (SNB) is a cluster of motoneurons in the lumbar spinal cord that innervates striated muscles in the perineum (2).…”

“…This was ruled out, however, by treating rats with testosterone perinatally. Whereas the testosterone treatment completely masculinized the SNB of wild-type females, it had no effect on the SNB system of males expressing functional androgen receptors only in muscle fibers (1). The work is doubly satisfying in that it uses a fresh approach to address a long-standing question and comes up with a surprising answer.…”

“…Niel et al (1), however, now report on a new animal model designed to critically test the hypothesis that hormone action solely at androgen receptors in perineal muscle fibers is sufficient to masculinize the SNB. To do this, they crossed female rats carrying the Tfm mutation with transgenic males expressing the human androgen receptor gene driven by a skeletal muscle-specific promoter.…”

“…Work on the site of hormone action in the brain has largely been limited to describing where particular hormone receptors are expressed. The study by Niel et al (1) suggests that we may be in for some surprises when hypotheses about sites of hormone action are put to the test.…”

Subcellular effects of myocyte-specific androgen receptor overexpression in mice

“…Selective genetic ablation of AR within myocytes reduces lean body mass percentage (Ophoff et al 2009) and limb muscle strength and myofibrillar organization , although alterations in muscle size were not consistently observed in these studies. Similarly, selective overexpression of AR within myocytes of HSA-AR mice and rats using HSA-AR transgenes increases lean body mass percentage of these animals (Niel et al 2009, Fernando et al 2010. Intriguingly, the increase in lean body mass percentage in HSA-AR mice is associated with drastic reductions in overall body mass and with muscle wasting and weakness (Monks et al 2007).…”