Overexpression of Androgen Receptors in Target Musculature Confers Androgen Sensitivity to Motoneuron Dendrites

Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
Endocrinology (Impact Factor: 4.5). 02/2011; 152(2):639-50. DOI: 10.1210/en.2010-1197
Source: PubMed


The dendritic arbors of spinal motoneurons are dynamically regulated by a variety of factors, and several lines of evidence indicate that trophic interactions with the target musculature are of central importance. In highly androgen-sensitive motoneuron populations, androgens are thought to regulate motoneuron dendrites through their action at the receptor-enriched target musculature. Using rats transgenically modified to overexpress androgen receptor (AR) in skeletal muscle, we directly tested the hypothesis that the enhanced expression of AR in the target musculature can underlie the androgenic regulation of motoneuron dendritic morphology. The morphology of motoneurons innervating the quadriceps muscle was examined in wild-type (WT) rats as well as in rats that had been transgenically modified to overexpress ARs in their skeletal musculature. Motoneurons innervating the vastus lateralis muscle of the quadriceps in gonadally intact male rats, and castrated males with or without androgen replacement, were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. In WT rats, quadriceps motoneuron dendrites were insensitive to hormonal manipulation. In contrast, quadriceps motoneuron dendrites in gonadally intact transgenic males were larger than those of WT males. Furthermore, overexpression of ARs in the quadriceps muscle resulted in androgen sensitivity in dendrites, with substantial reductions in dendritic length occurring after castration; this reduction was prevented with testosterone replacement. Thus, it appears that the androgen sensitivity of motoneuron dendrites is conferred indirectly via the enrichment of ARs in the musculature.

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    • "Recent work has demonstrated that there is a causal relationship between androgen receptor expression in the target musculature and degree of androgen sensitivity exhibited by the innervating motoneurons (Huguenard et al., 2011). By manipulating the expression of androgen receptors exclusively in the target musculature , androgen sensitivity was induced in a population of normally androgen-insensitive motoneuron dendrites , demonstrating that androgen sensitivity is directly conferred by receptor expression in the target musculature (Huguenard et al., 2011). Along with our findings, these results further implicate the importance of receptor expression in the target muscles for hormonal regulation of motoneuron morphology. "
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    ABSTRACT: The spinal cord of rats contains the sexually dimorphic, steroid-sensitive motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrite growth is dependent on gonadal steroids: dendrite growth is inhibited after castration, but supported in androgen- or estrogen-treated castrated males. Furthermore, estrogenic support of SNB dendrite growth is mediated by estrogen action at the target musculature, inhibited by estrogen receptor (ER) blockade at the muscle and supported by local estradiol treatment. However, this estrogenic support is restricted to the early postnatal period, after which the morphology of SNB dendrites is insensitive to estrogens. To test if the developmentally restricted effects of estrogens on SNB dendrite growth coincide with the transient expression of ER in the target musculature, ERα expression was assessed during development and in adulthood. ERα expression in extra-Muscle fiber cells was greatest from postnatal day 7 (P7) to P14 and declined after P21. Because this pattern of ERα expression coincided with the period of estrogen-dependent dendrite growth, we tested if limiting hormone exposure to the period of maximal ERα expression in extra-muscle fiber cells could fully support estrogen-dependent SNB dendrite growth. We restricted estradiol treatment in castrated males from P7 to P21 and assessed SNB dendritic morphology at P28. Treating castrates with estradiol implants at the muscle from P7 to P21 supported dendrite growth to normal levels through P28. These data suggest that the transient ERα expression in target muscle could potentially define the critical period for estrogen-dependent dendrite growth in SNB motoneurons. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2012.
    Full-text · Article · Jan 2013 · Developmental Neurobiology
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    • "In contrast, the dendritic extent of quadriceps motoneurons of transgenic HSA-AR males showed an enhanced response to androgen manipulations: sham-operated or castrated and androgen-maintained transgenic males had greater dendritic extent than sham-operated or androgen-maintained wt males. This effect was eliminated by castration without androgen maintenance, which equalized dendritic extent between wt and transgenic males [44]. Soma size was unaffected by androgen manipulations in either genotype [44]. "
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    ABSTRACT: Sexual differentiation of the nervous system occurs via the interplay of genetics, endocrinology and social experience through development. Much of the research into mechanisms of sexual differentiation has been driven by an implicit theoretical framework in which these causal factors act primarily and directly on sexually dimorphic neural populations within the central nervous system. This review will examine an alternative explanation by describing what is known about the role of peripheral structures and mechanisms (both neural and non-neural) in producing sex differences in the central nervous system. The focus of the review will be on experimental evidence obtained from studies of androgenic masculinization of the spinal nucleus of the bulbocavernosus, but other systems will also be considered.
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