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N G Forger

Publications and source records attributed to N G Forger.

At least 19 recordsLinked to original sources
PubMed2005

Cell death and sexual differentiation of the nervous system.

Sex differences in nuclear volume or neuron number often are attributed to the hormonal control of cell death. In the spinal nucleus of the bulbocavernosus, the central portion of the medial preoptic nucleus, and the principal nucleus of the bed nucleus of the stria terminalis testicular hormones decrease cell death during perinatal life, resulting in a male advantage in neuron number in adulthood. Conversely, males have more dying cells during development and fewer neurons in adulthood than do females in the anteroventral periventricular nucleus of the hypothalamus. This review discusses several limitations and unresolved issues in the literature on sexually dimorphic cell death, and identifies molecular mechanisms by which gonadal steroids may control cell survival. In particular, evidence is presented for the hormonal regulation of neurotrophic factors and involvement of Bcl-2 family proteins in the determination of sex differences in neuron number.

Animals↗
PubMed2002

Castration reduces motoneuron soma size but not dendritic length in the spinal nucleus of the bulbocavernosus of wild-type and BCL-2 overexpressing mice.

Motoneurons in the spinal nucleus of the bulbocavernosus (SNB) and their target muscles, bulbocavernosus and levator ani (BC/LA), constitute an androgen-sensitive neuromuscular system. Testosterone regulates SNB soma size, SNB dendritic length, and BC/LA muscle mass in adult male rats. Recent evidence indicates that the cell death-regulatory protein, Bcl-2, may also play a role in adult neural plasticity. The present study examined whether gonadal hormones and/or the Bcl-2 protein influence the morphology of the SNB neuromuscular system in adult B6D2F1 mice. In Experiment 1, adult wild-type and Bcl-2 overexpressing males were castrated and implanted with silastic capsules containing testosterone or left blank. Six weeks after castration, cholera toxin-horseradish peroxidase was injected into the BC muscle to label SNB dendrites. Animals were killed 48 h later, and BC/LA muscle mass, SNB soma size, and SNB dendritic arbors were examined. In Experiment 2, wild-type and Bcl-2 overexpressing males were castrated or sham castrated, implanted with testosterone-filled or blank capsules, and examined 12 weeks later. In both experiments, BC/LA muscle mass and SNB soma size were significantly reduced in castrates receiving blank capsules. Surprisingly, however, there was no effect of hormone manipulation on any of several measures of dendritic length. Thus, the dendritic morphology of SNB motoneurons appears to be relatively insensitive to circulating androgen levels in B6D2F1 mice. Bcl-2 overexpression did not influence BC/LA muscle mass, SNB soma size, or SNB dendritic length, indicating that the morphology of this neuromuscular system and the response to castration are not altered by forced expression of the Bcl-2 protein.

Animals↗
PubMed2001

Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons.

Target-derived neurotrophic factors are assumed to regulate motoneuron cell death during development but remain unspecified. Motoneuron cell death in the spinal nucleus of the bulbocavernosus (SNB) of rats extends postnatally and is controlled by androgens. We exploited these features of the SNB system to identify endogenously produced trophic factors regulating motoneuron survival. Newborn female rat pups were treated with the androgen, testosterone propionate, or the oil vehicle alone. In addition, females received trophic factor antagonists delivered either into the perineum (the site of SNB target muscles) or systemically. Fusion molecules that bind and sequester the neurotrophins (trkA-IgG, trkB-IgG, and trkC-IgG) were used to block activation of neurotrophin receptors, and AADH-CNTF was used to antagonize signaling through the ciliary neurotrophic factor receptor-alpha (CNTFRalpha). An acute blockade of trkB, trkC, or CNTFRalpha prevented the androgenic sparing of SNB motoneurons when antagonists were delivered to the perineum. Trophic factor antagonists did not significantly reduce SNB motoneuron number when higher doses were injected systemically. These findings demonstrate a requirement for specific, endogenously produced trophic factors in the androgenic rescue of SNB motoneurons and further suggest that trophic factor interactions at the perineum play a crucial role in masculinization of this neural system.

Androgens↗
PubMed2000

Ciliary neurotrophic factor increases muscle fiber number in the developing levator ani muscle of female rats.

In addition to its well characterized neurotrophic properties, ciliary neurotrophic factor (CNTF) also has myotrophic effects in several experimental paradigms. We have previously observed that the volume of the levator ani (LA) muscle is increased in female rats treated with CNTF during the perinatal period. In order to determine the cellular basis for the effect of CNTF on LA muscle volume, female rat pups were given daily perineal injections of CNTF or a control solution from postnatal day 1 through 6. Mean cross-sectional area of LA muscle fibers and LA fiber number were assessed on postnatal day 7. CNTF treatment increased LA muscle fiber number more than 300% while having no effect on LA fiber size. We conclude that CNTF prevents muscle fiber degeneration and/or increases myogenesis in the developing LA muscle.

Animals↗
PubMed2000

Additive effects of ciliary neurotrophic factor and testosterone on motoneuron survival; differential effects on motoneuron size and muscle morphology.

Testosterone and ciliary neurotrophic factor (CNTF) each enhance motoneuron survival in the spinal nucleus of the bulbocavernosus (SNB) of newborn rats. Here we directly compared the effects of CNTF and testosterone, alone and in combination, on SNB motoneuron number, SNB cell size, and morphology of the levator ani (LA) target muscle. Female rat pups were treated daily from postnatal day 1 through 6 (P1-P6) with recombinant human CNTF (hCNTF), testosterone propionate (TP), both hCNTF and TP, or neither. Effects of treatment were assessed on P7. TP and hCNTF each increased the number of SNB motoneurons and did so to a similar degree. Females treated with both hCNTF and TP had significantly more SNB cells than those receiving either hCNTF or TP alone. TP administered from P1 to P6 also increased SNB motoneuron size on P7. In contrast, hCNTF alone did not significantly affect SNB cell size, and hCNTF in combination with TP antagonized the effect of TP on motoneuron size. TP also increased LA muscle fiber number and LA fiber size, whereas hCNTF did not significantly influence LA muscle morphology in this study. Immunohistochemistry established that virtually all SNB motoneurons of both males and females express the CNTF alpha receptor (CNTFRalpha) between embryonic day 20 and postnatal day 6. Thus, effects of TP and hCNTF on SNB motoneuron survival were additive, and increases in motoneuron survival were dissociated from changes in target muscle morphology in hCNTF-treated animals. SNB motoneurons express CNTFRalpha perinatally and are therefore potential direct sites of hCNTF action.

Animals↗
PubMed1999

Effects of testosterone on the development of a sexually dimorphic neuromuscular system in ciliary neurotrophic factor receptor knockout mice.

Motoneurons in the spinal nucleus of the bulbocavernosus (SNB) innervate the perineal muscles, bulbocavernosus (BC), and levator ani (LA). Testosterone regulates the survival of SNB motoneurons and BC/LA muscles during perinatal life. Previous findings suggest that effects of testosterone on this system may be mediated by trophic factors-in particular, by a factor acting through the ciliary neurotrophic factor alpha-receptor (CNTFRalpha). To test the role of CNTFRalpha in the response of the developing SNB system to testosterone, CNTFRalpha +/+ and -/- mice were treated with testosterone propionate (TP) or oil during late embryonic development. BC/LA muscle size and SNB motoneuron number were evaluated on the day of birth. Large sex differences in BC and LA muscle size were present in newborn mice of both genotypes, but muscle volumes were reduced in CNTFRalpha -/- animals relative to same-sex, wild-type controls. Prenatal testosterone treatment completely eliminated the sex difference in BC/LA muscle size in wild-type animals, and eliminated the effect of the CNTFRalpha gene deletion on muscle size in males. However, the effect of TP treatment on BC and LA muscle sizes was blunted in CNTFRalpha -/- females. SNB motoneuron number was sexually dimorphic in oil-treated, wild-type mice. In contrast, there was no sex difference in SNB motoneuron number in oil-treated, CNTFRalpha knockout mice. Prenatal treatment with testosterone did not increase SNB motoneuron number in CNTFRalpha -/- mice, but also did not significantly increase SNB motoneuron number in newborn wild-type animals. These findings confirm the absence of a sex difference in SNB motoneuron number in CNTFRalpha -/- mice. Moreover, the CNTFRalpha gene deletion influences perineal muscle development and the response of the perineal muscles to testosterone. Prenatal TP treatment of CNTFRalpha -/- males overcomes the effects of the gene deletion on the BC and LA muscles without a concomitant effect on SNB motoneuron number.

Animals↗
PubMed1998

Ciliary neurotrophic factor receptor alpha in spinal motoneurons is regulated by gonadal hormones.

Ciliary neurotrophic factor receptor alpha (CNTFRalpha) is the ligand-binding component of the CNTF receptor. CNTFRalpha expression is essential for the normal development of spinal motoneurons and is required for the development of a sex difference in motoneuron number in androgen-sensitive perineal motoneurons. We used immunocytochemistry to examine the expression and hormone regulation of CNTFRalpha protein in the spinal nucleus of the bulbocavernosus (SNB), dorsolateral nucleus and retrodorsolateral nucleus of the lower lumbar spinal cord of adult rats. CNTFRalpha immunoreactivity (CNTFRalpha-IR) was observed in the somata and dendrites of virtually all motoneurons. In all three motor pools, the intensity of motoneuron soma labeling was greatest among gonadally intact males and was reduced in females and gonadectomized males. The density of CNTFRalpha-IR in neuropil also tended to be highest in intact males. Short-term (2 d) testosterone propionate treatment reversed the decline in the density of soma labeling in the SNB of castrated males but did not reverse any other effects of castration. Long-term hormone treatment, achieved by implanting males with testosterone capsules at the time of gonadectomy, prevented the decline in soma labeling in all motor pools and partially prevented the decline in neuropil label caused by castration. We conclude that expression of CNTFRalpha protein is androgen-regulated in spinal motoneurons.

Animals↗
PubMed1998

Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 2. Effects of prenatal anti-androgens.

Pregnant spotted hyaenas were treated with anti-androgens to interfere with the unusually masculine 'phallic' development that characterizes females of this species. The effects on genital morphology and plasma androgen concentrations of infants were studied during the first 6 months of life. Although there were consistent 'feminizing' effects of prenatal anti-androgen treatment on genital morphology in both sexes, such exposure did not produce males with extreme hypospadia, as it does in other species, nor did it produce females with a 'typical' mammalian clitoris and external vagina. 'Feminization' of males resulted in a penis with the morphological features of the hyaena clitoris, and 'feminization' of females exaggerated the sex differences that are typical of this species. The effects of treatment were present at birth and persisted for at least 6 months. Treatment of pregnant females with flutamide and finasteride also markedly reduced circulating concentrations of testosterone and dihydrotestosterone in maternal plasma during pregnancy. Plasma delta 4-androstenedione was reduced in the female, but not the male, infants of treated mothers, consistent with an epigenetic hypothesis previously advanced to explain hormonal 'masculinization' of females. The present 'feminizing' effects of prenatal anti-androgen treatment are consistent with contemporary understanding of sexual differentiation, which accounts for morphological variation between the sexes in terms of steroids. However, current theory does not account for the basic genital structure of females and the present data suggest that development of the male penis and scrotum, and the female clitoris and pseudoscrotum, in spotted hyaenas may involve both androgen-dependent and androgen-independent components.

5-alpha Reductase Inhibitors↗
PubMed1998

Expression and androgen regulation of the ciliary neurotrophic factor receptor (CNTFRalpha) in muscles and spinal cord.

We have previously observed that ciliary neurotrophic factor (CNTF) can prevent the degeneration of androgen-sensitive perineal motoneurons and their target muscles, the bulbocavernosus and levator ani (BC/LA), in perinatal female rats. Response to CNTF is dependent on the expression of the alpha component of the CNTF receptor (CNTFRalpha). In the present study, we examined the developmental profile and androgen regulation of CNTFRalpha gene expression in BC/LA muscle, thigh muscle, and lumbosacral spinal cord. CNTFRalpha mRNA was abundantly expressed in the BC/LA and thigh around the time of birth; expression declined progressively after birth and remained low into adulthood. In contrast, CNTFRalpha message remained high in the lumbosacral spinal cord throughout development. Androgen regulation of CNTFRalpha expression was examined in prenatal animals by administering the androgen receptor blocker hydroxyflutamide from embryonic days E18 through E21. Four days of androgen deprivation caused a significant up-regulation of CNTFRalpha mRNA in the BC/LA, thigh, and spinal cord of male fetuses. After castration in adulthood, CNTFRalpha expression in the BC/LA transiently increased, then decreased below control levels. Expression of CNTFRalpha in thigh muscles and the lumbosacral spinal cord was not affected by adult castration. Thus, the perineal muscles and motoneurons are potential sites of direct CNTF action, and expression of the CNTFRalpha gene is modulated by androgen, especially in the androgen-sensitive perineal muscles. Transient up-regulation of CNTFRalpha following castration or androgen receptor blockade may represent a protective response designed to counteract the muscle atrophy normally induced by androgen withdrawal.

Androgens↗
PubMed1997

Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary neurotrophic factor receptor.

Ciliary neurotrophic factor (CNTF) has potent survival-promoting effects on motoneurons in vitro and in vivo. We examined knockout mice with null mutations of the gene for either CNTF itself or the alpha-subunit of the CNTF receptor (CNTFRalpha) to assess whether CNTF and/or its receptors are involved in the development of a sexually dimorphic neuromuscular system. Male rodents have many more motoneurons in the spinal nucleus of the bulbocavernosus (SNB) than do females. This sex difference is caused by hormone-regulated death of SNB motoneurons and their target muscles. Sexual dimorphism of SNB motoneuron number developed completely normally in CNTF knockout (CNTF -/-) mice. In contrast, a sex difference in the SNB was absent in CNTFRalpha -/- animals: male mice lacking a functional CNTF alpha-receptor had fewer than half as many SNB motoneurons than did wild-type males and no more than did their female counterparts. Size of the bulbocavernosus and levator ani muscles, the main targets of SNB motoneurons, was not affected in either CNTF or CNTFRalpha knockout males. These observations suggest that signaling through the CNTF receptor is involved in sexually dimorphic development of SNB motoneuron number and that target muscle survival per se is not sufficient to ensure motoneuron survival in this system. In addition, our observations are consistent with the suggestion that CNTF itself is not the only endogenous ligand for the CNTF receptor. A second, as yet unknown, ligand may be important for neural development, including sexually dimorphic motoneuron development.

Androgens↗
PubMed1996

Sexual dimorphism of perineal muscles and motoneurons in spotted hyenas.

Female spotted hyenas are known for their male-like genitalia, high levels of aggression, and dominance over males, characteristics which are attributed to exposure to elevated levels of testosterone in utero. Although the nervous system of spotted hyenas has not previously been examined, one might predict that neural systems which are sexually dimorphic in other mammals would be monomorphic in this species. Spinal motoneurons which innervate muscles associated with the phallus are located in Onuf's nucleus and are more numerous in males than in females in a wide array of mammals. Onuf's nucleus was examined in adult and neonatal spotted hyenas and, contrary to expectation, was found to be sexually dimorphic in the typical mammalian pattern: Males have significantly more motoneurons in Onuf's nucleus than do females. This dimorphism was correlated with a previously undescribed dimorphism in the relevant target musculature. Specifically, the morphology of the bulbocavernosus muscle is distinctly different in male and female spotted hyenas. Pregnant hyenas were treated with anti-androgen in an attempt to interfere with the actions of androgen during fetal development. Motoneuron number in Onuf's nucleus and the morphology of the bulbocavernosus muscle were feminized in males exposed to anti-androgen in utero.

Androgen Antagonists↗
PubMed1996

Intrauterine position affects motoneuron number and muscle size in a sexually dimorphic neuromuscular system.

The intrauterine position occupied by a rodent fetus influences the amount of testosterone to which it is exposed before birth. Animals that are gestated between two male fetuses (2M) are exposed to higher circulating levels of testosterone than are animals positioned between two female fetuses (2F) and there are reliable differences in the reproductive physiology and behavior of 2M and 2F animals when adult. To determine whether intrauterine position modifies development of the central nervous system, we examined the sexually dimorphic spinal nucleus of the bulbocavernosus (SNB) in male and female gerbils from known intrauterine positions. We found that adult 2M female gerbils had 16% more SNB motoneurons than did 2F females. 2M males did not differ from 2F males in SNB motoneuron number, but the bulbocavernosus muscle, which is innervated by SNB motoneurons, was approximately 50% larger in 2M than in 2F males. These data indicate that intrauterine position can influence the morphology of the sexually dimorphic SNB neuromuscular system.

Animals↗
PubMed1996

Short- and long-term effects of ciliary neurotrophic factor on androgen-sensitive motoneurons in the lumbar spinal cord.

Motoneuron death in the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN) of the lumbar spinal cord is androgen regulated. As a result, many more SNB and DLN motoneurons die in perinatal female rats than in males, whereas treatment of newborn females with androgen results in a permanent sparing of the motoneurons and their target muscles. We previously observed that a neurotrophic molecule, ciliary neurotrophic factor (CNTF), also arrests the death of SNB motoneurons and their target musculature, at least in the short term. The present study compares the short- and long-term consequences of perinatal CNTF treatment on motoneuron number in the SNB, the DLN, and the retrodorsolateral nucleus (RDLN), a motor pool in the lower lumbar cord that does not exhibit hormone-regulated cell death. Female pups were treated with CNTF or vehicle alone from embryonic day 22 through postnatal day 6 (P6). Motoneuron number in the each nucleus was then determined immediately after treatment on P7, or 10 weeks later (P77). CNTF treatment significantly elevated motoneuron number in the SNB and DLN on P7; the volume of SNB target muscles on P7 was also greater in the CNTF-treated group. These effects were transient, however, as motoneuron number and ratings of muscle size were not different in CNTF-and vehicle-treated females on P77. Perinatal CNTF treatment did not alter cell number in the RDLN at either age. The finding that effects of CNTF on SNB and DLN motoneuron number are short lived contrasts with the permanent effects of early androgen treatment, and has implications for molecular models of the actions of androgen and neurotrophic factors on the developing spinal cord.

Age Factors↗
PubMed1995

Ciliary neurotrophic factor arrests muscle and motoneuron degeneration in androgen-insensitive rats.

Steroid hormones and neurotrophic factors exert profound and widespread effects on the developing nervous system, including regulation of the size, connectivity, and survival of neurons. Androgenic control of the survival of motoneurons in the spinal nucleus of the bulbocavernosus (SNB) of rats has been well documented. We previously found that ciliary neurotrophic factor (CNTF) mimics many effects of androgen on the developing SNB. Whether effects of CNTF depend on the presence of a functional androgen receptor was evaluated in the present study. Androgen-insensitive male rats bearing the testicular feminization mutation, Tfm, and female litter-mates were treated with CNTF or with vehicle alone from embryonic day 22 through postnatal day 3. On postnatal day 4 SNB cell number was elevated in both groups receiving CNTF. Volumes of the bulbocavernosus (BC) and levator ani (LA) muscles, targets of SNB motoneurons, were also markedly increased by CNTF. Since the BC appears to degenerate completely in untreated females, these results indicate that CNTF can delay or prevent muscle fiber death. The relative sparing of muscles and motoneurons did not differ for Tfm males and females, demonstrating that effects of CNTF on the SNB neuromuscular system do not require functional androgen receptors.

Animals↗
PubMed1993

Ontogeny of calcitonin gene-related peptide immunoreactivity in rat lumbar motoneurons: delayed appearance and sexual dimorphism in the spinal nucleus of the bulbocavernosus.

Immunoreactivity for calcitonin gene-related peptide (CGRP) has been observed in both adult and embryonic rat motoneurons. However, the developmental pattern of CGRP expression in motoneurons has not been systematically examined and the role of CGRP in neuromuscular development is poorly understood. We have mapped the ontogeny of CGRP-like immunoreactivity in three motoneuron pools of the rat lumbar spinal cord from birth through adulthood. Immunoreactivity was uniformly high in lateral horn motoneurons (the retrodorsolateral nucleus) of males and females at all ages examined. The majority of motoneurons of the dorsolateral nucleus also were positive throughout postnatal development although the percentage of positive motoneurons was slightly higher in males than in females. In contrast, virtually no motoneurons of the spinal nucleus of the bulbocavernosus, located in the medial ventral horn, were positive for CGRP in neonatal rats. CGRP-like immunoreactivity was delayed in this nucleus until approximately postnatal day 6 in males and day 27 in females. Because these three motoneuronal nuclei are differentially sensitive to early androgen and differ with respect to the timing of several developmental milestones, these observations have implications for the regulation and possible roles of CGRP in developing motor systems.

Androgens↗
PubMed1993

Ciliary neurotrophic factor maintains motoneurons and their target muscles in developing rats.

Ciliary neutrophic factor (CNTF) can enhance motoneuron survival during naturally occurring cell death in the chick (Oppenheim et al, 1991). Because receptors for CNTF are expressed in both motoneurons and their target muscles (Davis et al., 1991; lp et al., 1993), both tissues are potential sites of CNTF action in development. We examined the ability of CNTF to prevent the degeneration of a neuromuscular system in developing female rats. The death of motoneurons in the spinal nucleus of the bulbocavernosus (SNB) extends postnatally and is sexually dimorphic, with many more motoneurons dying in females than in males. The bulbocavernosus (BC), a target muscle of SNB motoneurons, also degenerates postnatally in females. Female rats treated with daily injections of 1 microgram CNTF from embryonic day 22 through postnatal day 3 (P3) had 70% more SNB motoneurons on P4 than did control animals, and the number of pyknotic profiles in the SNB area was markedly reduced by CNTF. In addition, the degeneration of the BC was completely prevented by CNTF treatment of perinatal female rats. These results demonstrate that CNTF can preserve mammalian motoneurons from developmental death, but also suggest that the sparing effect of CNTF on motoneurons in vivo may be a secondary consequence of effects on target muscles.

Analysis of Variance↗
PubMed1992

Regulation of motoneuron death in the spinal nucleus of the bulbocavernosus.

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.

Animals↗