Aromatase inhibition reduces dendritic growth in a sexually dimorphic rat spinal nucleus

The rat lumbar spinal cord contains the steroid-sensitive spinal nucleus of the bulbocavernosus (SNB), whose motoneurons innervate perineal muscles involved in copulatory reflexes. In normal males, SNB motoneuron dendrites grow exuberantly through postnatal (P) day 28. This growth is steroid dependent: Dendrites fail to grow in males castrated at P7, but grow normally in castrates treated with testosterone or its metabolites, dihydrotestosterone combined with estrogen. Treatment with either metabolite alone supports dendritic growth, but not to the level of testosterone-treated or intact males. In this study, we tested the hypothesis that aromatization of androgens to estrogens was involved in the masculine development of SNB dendrites. Motoneuron morphology was assessed in normal males and males treated daily (P7-28) with fadrozole, a potent aromatase inhibitor (0.25 mg/kg, subcutaneously) or saline vehicle (n = 4-6/group). SNB motoneurons were retrogradely labeled with cholera toxin-horseradish peroxidase at P28 (when dendritic length is normally maximal) and reconstructed in three dimensions. Comparable labeling was seen across groups; it was equivalent in both the rostrocaudal and radial extents. However, dendritic lengths in fadrozole-treated males were significantly below those of intact or saline-treated males. Neither SNB somata size nor target muscle weight differed across groups. These results suggest that aromatization of androgens to estrogens is necessary for development of masculine SNB dendritic morphology.     

Castration‐induced upregulation of muscle ERα supports estrogen sensitivity of motoneuron dendrites in a sexually dimorphic neuromuscular system

The spinal cord of rats contains the sexually dimorphic motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrites fail to grow after castration, but androgen or estrogen treatment supports dendritic growth in castrated males. Estrogenic support of SNB dendrite growth is mediated by estrogen receptors (ER) in the target muscle. ERα expression in cells lacking a basal lamina (referred to as “extra‐muscle fiber cells”) of the SNB target musculature coincides with the period of estrogen‐dependent SNB dendrite growth. In the SNB target muscle, extra‐muscle fiber ERα expression declines with age and is typically absent after postnatal (P) day 21 (P21). Given that estradiol downregulates ERα in skeletal muscle, we tested the hypothesis that depleting gonadal hormones would prevent the postnatal decline in ERα expression in the SNB target musculature. We castrated male rats at P7 and assessed ERα immunolabeling at P21; ERα expression was significantly greater in castrated males compared with normal animals. Because ERα expression in SNB target muscles mediates estrogen‐dependent SNB dendrogenesis, we further hypothesized that the castration‐induced increase in muscle ERα would heighten the estrogen sensitivity of SNB dendrites. Male rats were castrated at P7 and treated with estradiol from P21 to P28; estradiol treatment in castrates resulted in dendritic hypertrophy in SNB motoneurons compared with normal males. We conclude that early castration results in an increase in ERα expression in the SNB target muscle, and this upregulation of ERα supports estrogen sensitivity of SNB dendrites, allowing for hypermasculinization of SNB dendritic arbors. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 921–935, 2013     

Testosterone metabolites differentially maintain adult morphology in a sexually dimorphic neuromuscular system

The lumbar spinal cord of rats contains the sexually dimorphic, steroid‐sensitive spinal nucleus of the bulbocavernosus (SNB). Androgens are necessary for the development of the SNB neuromuscular system, and in adulthood, continue to influence the morphology and function of the motoneurons and their target musculature. However, estrogens are also involved in the development of the SNB system, and are capable of maintaining function in adulthood. In this experiment, we assessed the ability of testosterone metabolites, estrogens and nonaromatizable androgens, to maintain neuromuscular morphology in adulthood. Motoneuron and muscle morphology was assessed in adult normal males, sham‐castrated males, castrated males treated with testosterone, dihydrotestosterone, estradiol, or left untreated, and gonadally intact males treated with the 5α‐reductase inhibitor finasteride or the aromatase inhibitor fadrozole. After 6 weeks of treatment, SNB motoneurons were retrogradely labeled with cholera toxin‐HRP and reconstructed in three dimensions. Castration resulted in reductions in SNB target muscle size, soma size, and dendritic morphology. Testosterone treatment after castration maintained SNB soma size, dendritic morphology, and elevated target muscle size; dihydrotestosterone treatment also maintained SNB dendritic length, but was less effective than testosterone in maintaining both SNB soma size and target muscle weight. Treatment of intact males with finasteride or fadrozole did not alter the morphology of SNB motoneurons or their target muscles. In contrast, estradiol treatment was completely ineffective in preventing castration‐induced atrophy of the SNB neuromuscular system. Together, these results suggest that the maintenance of adult motoneuron or muscle morphology is strictly mediated by androgens. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 70: 206–221, 2010.     

Hormonally mediated plasticity of motoneuron morphology in the adult rat spinal cord: A cholera toxin-HRP study

The dorsolateral nucleus (DLN) and the spinal nucleus of the bulbocavernosus (SNB) of the rat lumbar spinal cord are sexually dimorphic groups of motoneurons that innervate striated perineal muscles involved in male copulatory behavior. Androgens control the development of these motoneurons and their target muscles, and continue to influence the system in adulthood. Given that several features of SNB motoneuron morphology have been shown to be androgen sensitive in adult male rats, we examined the effects of androgen manipulations on the morphology of motoneurons in the DLN in adult rats. Adult male rats were castrated and implanted with testosterone-filled or blank implants, or were subjected to a sham-castration procedure. Six weeks after treatment, motoneurons in the DLN were retrogradely labeled with cholera toxin-horseradish peroxidase (HRP) after injection into the ischiocavernosus (IC) muscle and their morphology assessed. Measures of the radial extent and coverage of the dendritic arbor of DLN motoneurons projecting to the IC (DLN-IC motoneurons) were similar across the groups, indicating comparable degrees of HRP transport. However, DLN-IC motoneurons in castrates with blank implants possessed both shorter dendritic lengths and smaller somas than those of castrates treated with testosterone. Castrates with testosterone implants had DLN-IC motoneurons that were significantly larger than those of sham castrates in dendritic length and soma area. These results suggest that motoneurons in the DLN, like those in the SNB, possess a significant degree of structural plasticity in adulthood which is influenced by androgens.     

Tactile stimulation during artificial rearing influences adult function and morphology in a sexually dimorphic neuromuscular system

Maternal licking of rat pups affects the development of the spinal nucleus of the bulbocavernosus (SNB), a sexually dimorphic motor nucleus that controls penile reflexes involved with copulation. Maternal licking influences SNB motoneurons, with reductions in licking producing decreased SNB number, size, and dendritic length in adulthood. Reduced maternal licking also produces deficits in adult male copulatory behavior. In this experiment, we used an artificial rearing paradigm to assess the potential role of tactile stimulation in mediating the effects of maternal licking on the SNB neuromuscular system. During artificial rearing, pups were stroked with a paintbrush to mimic maternal licking, receiving low, medium, or high levels of daily stimulation. In adulthood, ex copula penile reflex behavior was tested and the morphology of SNB motoneurons assessed. SNB motoneurons were retrogradely labeled with cholera toxin-conjugated HRP and dendritic arbor was reconstructed in three dimensions. Animals that received low levels of stimulation showed deficits in penile reflexes relative to maternally reared controls, including a longer latency to erection, fewer cup erections, and fewer erection clusters. SNB dendritic morphology was also shaped by stimulation condition, with animals that received low or medium levels of stimulation showing an average 27% reduction in dendritic length. In addition, several reflex behaviors were significantly correlated with dendritic length, including latency to first erection, percent of cup erections, and number of erection clusters. These results suggest that tactile stimulation provided by maternal licking mediates some of the effects of maternal care on the development of male copulatory behavior.     

Differential sensitivity to androgens within a sexually dimorphic muscle of male frogs (Xenopus laevis)

Male frogs use their forelimb flexor muscles to clasp females during the mating behavior known as amplexus. We investigated the effects of testosterone on a principal forelimb flexor, the flexor carpi radialis muscle (FCR), using morphological and histochemical techniques. Male Xenopus laevis were surgically manipulated to produce high or low levels of circulating testosterone for an 8-week period. After this treatment, measurement of fibers in muscle cross-sections revealed that average fiber size was positively correlated with testosterone level. This effect was not the same for all muscle fibers, however. Fibers in the shoulder region were more sensitive to testosterone than fibers in other regions of the muscle. Histochemical staining of cross-sections showed that the patterns of staining for myosin ATPase or succinic dehydrogenase (SDH) were not influenced by testosterone levels, but total SDH activity was increased by testosterone treatment. When sensitivity to testosterone was correlated with ATPase activity, fibers with high ATPase activity were found to be more sensitive to testosterone than fibers with low activity, regardless of position within the muscle. Most fibers with high ATPase activity were located in the shoulder region of the muscle. These fibers are innervated by different motor axons than are fibers in the elbow region of the muscle, and contractions of shoulder (but not elbow) region fibers, elicited by stimulation of motor axons, are slowed by testosterone treatment (Regnier and Herrera, 1993, J. Physiol. 461:565–581). © 1993 John Wiley & Sons, Inc.     

Differential effects of the perinatal steroid environment on three sexually dimorphic parameters of the rat brain

Gonadectomy of male rats was performed at 0, 6-7 (6h), 12-13 (12h), or 24 h postnatally in order to examine the influence of testosterone exposure on sexual differentiation of the brain. The indices examined were: the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) titers following estradiol benzoate (EB) and progesterone (P) administration. Control animals were sham-operated at 0 h and gonadectomized at 29 days of age (sham). A decrease in the percentage of males with elevated plasma LH levels following P was found with increasing delay before gonadectomy. Significant (P less than 0.001) differences existed in the amplitude of plasma LH titers 5 h following P administration between sham, 0 h, and 6 h groups. Follicle-stimulating hormone was also elevated in all neonatally gonadectomized male groups following P administration, but there was no difference between the groups. Volume of the SDN-POA was significantly (P less than 0.001) smaller in all gonadectomized males when compared to that of sham-operated males, but no differences existed between males gonadectomized at the different hours postpartum. In female rats gonadectomized at 0 h (F0h), LH levels were elevated 5 h following P, but only to a magnitude of 36% of that of sham-operated controls (P less than 0.001). Volume of the SDN-POA of the F0h group was significantly reduced (P less than 0.05) when compared to that of sham females. Thus, in males, the presence of the tests prenatally may be responsible for the initiation of masculinization of LH release mechanisms and the SDN-POA, but both require further androgen exposure for their completion. In addition, the LH and FSH regulating systems show a differential sensitivity to the steroid hormone environment during development that shapes the animal's response to steroid as an adult.     

Maternal care effects on the development of a sexually dimorphic motor system: The role of spinal oxytocin

Maternal licking in rats affects the development of the spinal nucleus of the bulbocavernosus (SNB), a sexually dimorphic motor nucleus that controls penile reflexes involved with copulation. Reduced maternal licking results in decreased motoneuron number, size, and dendritic length in the adult SNB, as well as deficits in adult male copulatory behavior. Our previous findings that licking-like tactile stimulation influences SNB dendritic development and upregulates Fos expression in the lumbosacral spinal cord suggest that afferent signaling is changed by differences in maternal stimulation. Oxytocin afferents from the hypothalamus are a possible candidate, given previous research that has shown oxytocin is released following sensory stimulation, oxytocin modulates excitability in the spinal cord, and is a pro-erectile modulator of male sex behavior. In this experiment, we used immunofluorescence and immediate early gene analysis to assess whether licking-like tactile stimulation of the perineum activated parvocellular oxytocinergic neurons in the hypothalamus in neonates. We also used enzyme immunoassay to determine whether this same stroking stimulation produced an increase in spinal oxytocin levels. We found that stroking increased Fos immunolabeling in small oxytocin-positive cells in the paraventricular nucleus of the hypothalamus, in comparison to unstroked or handled control pups. In addition, 60 s of licking-like perineal stimulation produced a transient 89% increase in oxytocin levels in the lumbosacral spinal cord. Together, these results suggest that oxytocin afferent activity may contribute to the effects of early maternal care on the masculinization of the SNB and resultant male copulatory behavior.     

Trophic effects of androgen: development and hormonal regulation of neuron number in a sexually dimorphic vocal motor nucleus.

In Xenopus laevis, the laryngeal motor nucleus (n. of cranial nerves IX-X) is part of a sexually differentiated, androgen sensitive neuromuscular system devoted to vocalization. Adult males have more n. IX-X neurons than females; however, during development of n. IX-X, the rate of neurogenesis does not appear to differ between the sexes. In this study, we explored the role of naturally occurring cell death in the development of this nucleus and asked whether cell death might be involved in establishing the sex difference in neuron number. Counts of n. IX-X neurons reveal that at tadpole stage 56, males and females have similar numbers of n. IX-X neurons, but by stage 64 male neuron numbers are greater. This sex difference arises owing to a greater net loss of neurons in females-males lose approximately 25% of their n. IX-X neurons between stages 56 and 64, while females lose approximately 47%. Sexual differentiation of n. IX-X neuron number coincides with a period of developmental cell death, as evidenced by terminal transferase-mediated dUTP nick-end labeling and the presence of pyknotic nuclei in n. IX-X. A role for gonadal hormones in controlling cell number was examined by treating tadpoles with exogenous androgen and determining the number of n. IX-X neurons at stage 64. Dihydrotestosterone (DHT) treatment from the beginning of the cell death period (stage 54) until stage 64 had no effect on the number of n. IX-X neurons in males but did significantly increase n. IX-X neuron number in females. This increase was sufficient to abolish the sex difference normally observed at stage 64. Although DHT induced increases in female neuron number, it did not induce increases in cell proliferation or addition of newly born neurons to n. IX-X. DHT may therefore have increased neuron number by protecting cells from death. We conclude that androgens can influence the survival of n. IX-X neurons during a period of naturally occurring cell death, and that this action of androgen is critical to the development of sex differences in n. IX-X neuron number.     

Dietary restriction induces a sexually dimorphic type I interferon response in mice with gene-environment interactions

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Estrogenic support of motoneuron dendritic growth via the neuromuscular periphery in a sexually dimorphic motor system

The lumbar spinal cord of rats contains the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB). In males, the growth of SNB dendrites is steroid-dependent: dendrites fail to grow after castration, but grow in castrates treated with androgens or estrogens. Blocking estradiol synthesis or estrogen receptors in gonadally intact males attenuates SNB dendritic growth, suggesting that estrogens are required and must be able to act at their receptors to support normal masculine dendritic growth. However, SNB motoneurons do not accumulate estrogens, suggesting that estrogens act indirectly to support SNB dendritic growth. In this experiment, we examined whether local estrogen action in the neuromuscular periphery was involved in the postnatal development of SNB motoneurons. Motoneuron morphology was assessed in gonadally intact and castrated males. Gonadally intact males were left untreated or given either blank or tamoxifen implants sutured to the target musculature, or tamoxifen interscapular implants. Castrated males were left untreated or were given estradiol by muscle or interscapular implants or systemic injection during the period of SNB dendritic growth. At postnatal day 28, when SNB dendritic length is normally maximal, SNB motoneurons were retrogradely labeled with cholera toxin-HRP and reconstructed in three dimensions. While interscapular tamoxifen implants were ineffective, blocking estrogen receptors at the target musculature resulted in attenuation of SNB dendritic growth. In contrast, while interscapular implants of estradiol were ineffective, local treatment with estradiol at the target musculature in castrated males resulted in masculinization of dendritic growth. Thus, estrogens may act by an indirect action in the neuromuscular periphery to support SNB dendritic growth.     

Hormonal control of neuron number in sexually dimorphic spinal nuclei of the rat: IV. Masculinization of the spinal nucleus of the bulbocavernosus with testosterone metabolites

The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic motor nucleus in the rat lumbar spinal cord. SNB motoneurons and their perineal target muscles are present in adult males but reduced or absent in females. This sexual dimorphism is due to the presence of androgen during development; females treated with testosterone (T) perinatally have a masculine SNB system. To assess whether masculinization of the SNB could involve the conversion of testosterone into its active metabolites, dihydrotestosterone (DHT) and estrogen, we examined the development of the SNB in females treated perinatally with estrogen alone or in combination with dihydrotestosterone. Counts of motoneurons in the developing SNB in all groups showed the typical prenatal increase followed by a differential postnatal decline; the incidence of degenerating cells reflected this decline. Motoneuron numbers and the frequency of degenerating cells in females treated with estrogen (E) alone did not differ from those of normal females, with both groups losing large numbers of motoneurons and having a high incidence of degenerating cells. In contrast, females treated with both estrogen and dihydrotestosterone did not show the female-typical decline in motoneuron number and had a low, masculine incidence of degenerating cells. By postnatal day 10, females treated with estrogen and dihydrotestosterone had a fully masculine SNB motoneuron number, suggesting that dihydrotestosterone alone or in conjunction with estrogen may be involved in the development of the sexually dimorphic SNB system.     

Differential effects of testosterone metabolites upon the size of sexually dimorphic motoneurons in adulthood.

This study examined the effect of testosterone and two of its metabolites on the size of motoneurons in the sexually dimorphic spinal nucleus of the bulbocavernosus (SNB) in adult male rats. Treatment of castrates with either testosterone or dihydrotestosterone maintained SNB cell size, although testosterone was more effective in this regard. However, estradiol, either alone or in conjunction with dihydrotestosterone treatment, had no effect on the size of the somata or nuclei of SNB motoneurons. These results indicate that testosterone affects SNB cell size by interacting with androgen receptors and that aromatized metabolites of testosterone are not involved in this aspect of motoneuronal plasticity in adulthood. Because the penile reflexes mediated by the SNB neuromuscular system are also sensitive to androgen but not estrogen treatment, morphological changes in SNB cells may contribute to the androgenic modulation of these reflexes.     

Differential effects of testosterone,dihydrotestosterone and estradiol on carotenoid deposition in an avian sexually selected signal

Recent studies have demonstrated that carotenoid-based traits are under the control of testosterone (T) by up-regulation of carotenoid carriers (lipoproteins) and/or tissue-specific uptake of carotenoids. T can be converted to dihydrotestosterone (DHT) and estradiol (E2), and variation in conversion rate may partly explain some contradictory findings in the literature. Moreover, most studies on the effect of T on sexual signals have focused on the male sex only, while in many species females show the same signal, albeit to a lesser extent. We studied the effects of T, DHT, and E2 treatment in male and female diamond doves Geopelia cuneata in which both sexes have an enlarged red eye ring, which is more pronounced in males. We first showed that this periorbital ring contains very high concentration of carotenoids, of which most are lutein esters. Both T and DHT were effective in enhancing hue, UV-chroma and size in both sexes, while E2 was ineffective. However, E2 dramatically increased the concentration of circulating lipoproteins. We conclude that in both sexes both color and size of the secondary sexual trait are androgen dependent. The action of androgens is independent of lipoproteins regulation. Potential mechanisms and their consequences for trade-off are discussed.     

Steroid accumulation in song nuclei of a sexually dimorphic duetting bird,the rufous and white wren

This study tested the hypothesis that the relative proportion of neurons that are hormone sensitive in avian song control nuclei is related to the basic motor ability to sing, whereas the absolute number of such neurons is related to the complexity of song behavior. Either [³H]testosterone (T) or estradiol (E₂) was injected into male and female rufous and white wrens (Thryothorus rufalbus), a tropical species in which females sing duets with males but have smaller song repertoires than males. Autoradiographic analysis indicated that there were no sex differences in the proportions of T or E₂ target cells in two song nuclei: the high vocal center (HVC) and the lateral portion of the magnocellular nucleus of the anterior neostriatum (IMAN). The density of labeled cells per unit volume of tissue did not differ between the sexes in either song nucleus. Males have larger song nuclei, however, which is consistent with their more complex song behavior, and therefore have a greater total number of hormone-sensitive neurons in these regions than do females. Comparison of these results with measures of hormone accumulation in zebra finches, canaries, and bay wrens supports the hypothesis presented. © 1996 John Wiley & Sons, Inc.     

Androgen regulation of neuromuscular junction structure and function in a sexually dimorphic muscle of the frog Xenopus laevis

Specific forelimb muscles in anurans are sexually dimorphic and underlie the androgen-dependent clasping response of males during amplexus. Previous studies have reported that androgen treatment slows the contractile properties of these sexually dimorphic forelimb muscles. In amphibians, the expression of functionally distinct acetycholine (ACh) receptors, the levels of acetylcholinesterase (AChE), the extent of multiple innervation, and the structure of individual end plates vary with the contractile properties of the muscle fibers. In higher vertebrates, androgens have been reported to alter the expression of ACh receptors, AChE, and the neuromodulator, calcitonin gene-related peptide (CGRP). To determine whether the known androgen-dependent changes in contraction of androgen-sensitive forelimb muscles are accompanied by concomitant changes in synaptic structure or function, we have compared functional neuromuscular transmission, the pattern of innervation, and CGRP immunoreactivity in nerve or muscle preparation from castrated (C) and castrated and testosterone-treated (CT) adult male Xenopus laevis. CGRP expression in androgen receptor (AR)-immunopositive neurons was increased in CT animals. However, no significant differences were found in ACh-mediated single channel or macroscopic currents, the extent of multiple end plates, or end plate morphology for forelimb fibers isolated from C and CT Xenopus. In contrast, analysis of forelimb fibers from gonadally intact adult females and juvenile animals of both sexes revealed that macroscopic synaptic currents were significantly shorter in these animals than in either C or CT adult males. Our data suggest that forelimb fibers in sexually dimorphic muscles of Xenopus do show significant differences in synaptic transmission; however, neither end-plate organization nor functional neuromuscular transmission are subject to activational effects of androgens in adult male frogs. © 1995 John Wiley & Sons, Inc.     

Trophic effects of androgen: Development and hormonal regulation of neuron number in a sexually dimorphic vocal motor nucleus

In Xenopus laevis, the laryngeal motor nucleus (n. of cranial nerves IX‐X) is part of a sexually differentiated, androgen sensitive neuromuscular system devoted to vocalization. Adult males have more n. IX‐X neurons than females; however, during development of n. IX‐X, the rate of neurogenesis does not appear to differ between the sexes. In this study, we explored the role of naturally occurring cell death in the development of this nucleus and asked whether cell death might be involved in establishing the sex difference in neuron number. Counts of n. IX‐X neurons reveal that at tadpole stage 56, males and females have similar numbers of n. IX‐X neurons, but by stage 64 male neuron numbers are greater. This sex difference arises owing to a greater net loss of neurons in females—males lose ∼25% of their n. IX‐X neurons between stages 56 and 64, while females lose ∼47%. Sexual differentiation of n. IX‐X neuron number coincides with a period of developmental cell death, as evidenced by terminal transferase‐mediated dUTP nick‐end labeling and the presence of pyknotic nuclei in n. IX‐X. A role for gonadal hormones in controlling cell number was examined by treating tadpoles with exogenous androgen and determining the number of n. IX‐X neurons at stage 64. Dihydrotestosterone (DHT) treatment from the beginning of the cell death period (stage 54) until stage 64 had no effect on the number of n. IX‐X neurons in males but did significantly increase n. IX‐X neuron number in females. This increase was sufficient to abolish the sex difference normally observed at stage 64. Although DHT induced increases in female neuron number, it did not induce increases in cell proliferation or addition of newly born neurons to n. IX‐X. DHT may therefore have increased neuron number by protecting cells from death. We conclude that androgens can influence the survival of n. IX‐X neurons during a period of naturally occurring cell death, and that this action of androgen is critical to the development of sex differences in n. IX‐X neuron number. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 375–385, 1999     

Absence of p53 and FasL has sexually dimorphic effects on both development and reproduction

Reproduction and development are highly dependent on apoptosis to balance the proliferation that necessarily occurs during these processes. How the absence of two apoptotic factors in mice would affect reproduction and development was examined. Given previous reports of increased neural tube defects in p53-/- female fetuses, decreased fertility in gld female mice, and altered spermatogenesis in both p53 and gld male mice, the possibility that these phenotypes might be enhanced by the elimination of a second apoptotic factor was investigated. The reproductive vigor and the health of offspring were monitored during the production of the new double-deficient strain (FasL-/-p53-/-) for any changes from the reported phenotypes. Thus, any unusual phenotypes that could lead to new models for studying mechanisms of health and disease would be identified. Double-deficient male offspring appeared healthy and occurred at expected frequencies. Additionally, spermatogenesis and male fertility were unaffected by the gene deficiencies. On the other hand, FasL+/+p53-/- and FasL-/-p53-/- female mice were susceptible to increased malformations and post-natal death. These abnormalities were consistent with previous reports of neural tube defects in p53-/- female mice. Fertility rates were also significantly decreased in p53-/- female mice that lived to be adults, an observation not previously reported. Finally, the absence of both FasL and p53 led to dystocia in pregnant female mice, suggesting that the two genes play complementary roles in parturition. Therefore, although male mouse development and reproduction remained unaffected by p53 and FasL deficiencies, female mouse development was adversely affected by the absence of p53, and no live litters were born to female mice with the combined absence of both FasL and p53. In this report, we suggest a potential mechanism involving corpora luteal regression to explain this defect in parturition in FasL-/-p53-/- female mice.     

Regulation of motoneuron death in the spinal nucleus of the bulbocavernsus

A sexual dimorphism in the number of motoneurons in the spinal nucleus of the bulbocavernosus (SNB) of rats is engendered by a sex difference in ontogenetic cell death. Testicular secretions, specifically androgenic steroids, reduce SNB motoneuron death in males. The fate of the target muscles generally mirrors that of the motoneurons, and androgens appear to exert their effects upon the target muscles, sparing the motoneurons as a secondary consequence. Treatment with ciliary neurotrophic factor can also spare SNB motoneurons in newborn females, raising the possibility that this factor normally mediates androgen's effect upon motoneuron survival. The ontogeny of calcitonin gene-related peptide immunoreactivity is delayed in SNB cells compared with other motoneurons and is further delayed in the SNB cells of females. In both sexes, calcitonin gene-related peptide is detected after the period of SNB motoneuron death is complete. A sex difference in motoneuron number is also seen in the human homologue of the SNB and, because ontogenetic death of motoneurons in humans overlaps the period of androgen secretion, may arise in a manner similar to that in the rat SNB. © 1992 John Wiley & Sons, Inc.