Androgenic Regulation of Expression of β‐Tubulin Messenger Ribonucleic Acid in Motoneurons of the Spinal Nucleus of the Bulbocavernosus

Matsumoto, Akira; Arai, Yasumasa; Hyodo, Susumu

doi:10.1111/j.1365-2826.1993.tb00495.x

Cited by 42 publications

(30 citation statements)

References 60 publications

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“…We speculate that testosterone affects axonal caliber, perhaps by influencing the number and/or properties of microtubules and/or neurofilaments (Marszalek et al, 1996;Hoffman et al, 1987). This view is consistent with the pathology of Kennedy disease, as well as with experimental findings of testosterone-induced upregula- tion of ␤-tubulin expression (Butler et al, 2001;Matsumoto et al, 1993). Future studies in experimental models are necessary to test directly the proposed hypothesis of testosteroneinduced increases in axonal diameter during adolescence.…”

Section: Discussionsupporting

confidence: 62%

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

et al. 2008

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The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n= 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath.

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Section: Discussionsupporting

confidence: 62%

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

et al. 2008

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“…There are additional effects of testosterone in neurons that require the androgen receptor (62). For example, testosterone activation of the androgen receptor increases the expression of cytoskeleton proteins, such as tubulin (63) and neuritin (64), which are important for neurite outgrowth and neuronal differentiation. Mutations of the androgen receptor that cause aggregation of polyglutamine-expanded protein induce cytotoxicity with normal levels of testosterone (65,66), a primary cause of Kennedy syndrome (67).…”

Section: Discussionmentioning

confidence: 99%

Elevated Testosterone Induces Apoptosis in Neuronal Cells

Estrada¹,

Varshney²,

Ehrlich

2006

Journal of Biological Chemistry

143

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Testosterone plays a crucial role in neuronal function, but elevated concentrations can have deleterious effects. Here we show that supraphysiological levels of testosterone (micromolar range) initiate the apoptotic cascade. We used three criteria, annexin V labeling, caspase activity, and DNA fragmentation, to determine that apoptotic pathways were activated by testosterone. Micromolar, but not nanomolar, testosterone concentrations increased the response in all three assays of apoptosis. signals lead to apoptotic cell death. These effects of testosterone on neurons will have long term effects on brain function.Neurosteroids have been implicated as components essential for the normal function of the central nervous system (1-4). The gonadal steroid hormones are required for reproductive function, but androgens also affect areas of the brain that are not primarily involved in reproduction such as the hippocampus (5), preoptic area, amygdala, and medial hypothalamic area (6). At physiological levels, androgens are involved in neuronal differentiation, neuroprotection, neuronal survival and development (7-9). These responses occur slowly (over hours) and are mediated through the intracellular androgen receptor. In the developing brain, androgens are capable of changing the ultrastructural characteristics of the neuronal plasma membrane with a relatively fast pace (10, 11). Recently, we have shown that nanomolar levels of testosterone induce rapid intracellular Ca 2ϩ increases in neuroblastoma cells (within seconds), which begin as Ca 2ϩ transients in the cytosol, propagate as waves of Ca 2ϩ in the cytoplasm and nucleus, and develop into an oscillatory pattern (12). These Ca 2ϩ signals depend on an interplay between Ca 2ϩ efflux from the endoplasmic reticulum through inositol 1,4,5-trisphosphate-sensitive Ca 2ϩ release channels (InsP 3 Rs) 4 and Ca 2ϩ reuptake into the endoplasmic reticulum by Ca 2ϩ pumps. This new testosterone-induced pathway in neuronal cells leads to neurite outgrowth (12), an essential event in neuronal differentiation (13). These results suggest an important physiological mechanism for the action of testosterone in neurons at physiological concentrations. However, it is unknown how these cells respond to high plasma levels of this neurosteroid, generally administered exogenously to achieve an increase in muscle mass (14, 15) or for replacement therapy (16). In vivo administration of large doses of androgens has been correlated with neurobehavioral changes like hyperexcitability, supra-aggressive nature, and suicidal tendencies (17, 18). These behavioral changes could be the outward manifestation of neuronal damage resulting from exposure to high concentrations of testosterone.In this investigation, we evaluated the hypothesis that high concentrations of testosterone can induce deleterious effects in neurons. We show that high levels of testosterone initiate an apoptotic program in neuroblastoma cells. Apoptosis is the normal and controlled process of cell death (19). Precise control of apoptos...

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“…Androgens are known to regulate several important biomolecules in the SNB. For example, levels of immunoreactivity for the ciliary neurotrophic factor receptor α (Forger et al, 1998) and BCL-2 (Zup and Forger, 2002) are androgendependent in SNB motoneurons, as are levels of mRNA expression for the major cytoskeletal elements β-actin (Matsumoto et al, 1992) and β-tubulin (Matsumoto et al, 1993). Moreover, the SNB target muscles also contain high numbers of androgen receptors (Monks et al, 2004), and androgens regulate a variety of characteristics of these muscles, including fiber size (Venable, 1966), neuromuscular junction size (Bleisch and Harrelson, 1989;Balice-Gordon et al, 1990), acetylcholine receptor number (Bleisch et al, 1982;Bleisch and Harrelson, 1989), muscle excitability (Foster and Sengelaub, 2004), and the number of functional calcium channels at the neuromuscular junction (Nudler et al, 2005).…”

Section: Androgenic Neuroprotection In the Snbmentioning

confidence: 99%

Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons

Fargo

Sengelaub

2007

Developmental Neurobiology

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Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have been investigating the effects of motoneuron loss on surviving motoneurons in a lumbar motor nucleus, the spinal nucleus of the bulbocavernosus (SNB). SNB motoneurons undergo marked dendritic and somal atrophy following the experimentally induced death of other nearby SNB motoneurons. However, treatment with testosterone at the time of lesioning attenuates this atrophy. Because testosterone can be metabolized into the estrogen estradiol (as well as other physiologically active steroid hormones), it was unknown whether the protective effect of testosterone was an androgen effect, an estrogen effect, or both. In the present experiment, we used a retrogradely transported neurotoxin to kill the majority of SNB motoneurons on one side of the spinal cord only in adult male rats. Some animals were also treated with either testosterone, the androgen dihydrotestosterone (which cannot be converted into estradiol), or the estrogen estradiol. As seen previously, partial motoneuron loss led to reductions in soma area and in dendritic length and extent in surviving motoneurons. Testosterone and dihydrotestosterone attenuated these reductions, but estradiol had no protective effect. These results indicate that the neuroprotective effect of testosterone on the morphology of SNB motoneurons following partial motoneuron depletion is an androgen effect rather than an estrogen effect.

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Androgenic Regulation of Expression of β‐Tubulin Messenger Ribonucleic Acid in Motoneurons of the Spinal Nucleus of the Bulbocavernosus

Cited by 42 publications

References 60 publications

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

Elevated Testosterone Induces Apoptosis in Neuronal Cells

Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons

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