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PubMed2000

Parent-progeny recognition as a function of MHC odortype identity.

The several linked polymorphic genes of the MHC, which has been proposed as a prime determinant of sensed genetic individuality within species, is known to operate in mice by olfactory recognition in aspects of reproductive behavior that concern mate selection, thereby favoring outbreeding and heterozygosity, and also concern the maintenance of pregnancy. A single base-change can alter an individual MHC odortype, and the potential range of combinatorial MHC-determined odortypes is clearly vast. Following our findings that newborn mice already express their MHC odortype (which is detectable at 9 days of gestational age), we sought to determine whether MHC is involved in behavioral aspects of early development, such as rearing. In the studies presented herein, we report the ability and proclivity of mothers to recognize and preferentially retrieve syngeneic (genetically identical) pups from other pups differing only for MHC. Reciprocally, we report the ability of pups to recognize their familial environment, regardless of whether they had been nursed by their biological mothers or by foster mothers. Early learning experiences of the MHC environment are apparently a key element in survival, assuring maternal protection and promoting outbreeding.

Animals↗
PubMed1985

Chemosensory recognition of mouse major histocompatibility types by another species.

Mice can recognize one another by individually characteristic body scents that reflect their genetic constitution at the extremely polymorphic major histocompatibility complex (MHC) of genes on chromosome 17. Reproductive behavioral manifestations of this sensory communication system include MHC-related mating preferences and neuroendocrine responses that affect preimplantation pregnancy and arise from the MHC-related scent of alien males. We have shown previously that mice can be trained in a Y maze to distinguish the scents of urine of congeneic mice that differ genetically only at the MHC. By means of an automated olfactometer, we now show that rats also can similarly distinguish the urinary scents of MHC congeneic mice. Thus, the mode of individual recognition that depends on scents determined by MHC genes can operate across species barriers.

Animals↗
PubMed1986

Participation of the murine X and Y chromosomes in genetically determined chemosensory identity.

The major histocompatibility complex of the mouse imparts to each mouse an odor that reflects its genetic constitution at this region of chromosome 17. Sensory recognition of these differential odors influences reproductive behavior and evokes neuroendocrine responses critical to the maintenance of pregnancy. To determine whether other parts of the mouse genome contribute to individual scent marking, and so may similarly exert a selective force on loci other than the major histocompatibility complex, mice differing genetically only in their X and/or Y chromosomes were tested for individuality of scent in the Y-maze system previously employed to investigate major histocompatibility complex-related scent distinctions. It is shown that the X and Y chromosomes each confer individually of scent related to genotype.

Animals↗
PubMed1990

Odor types determined by the major histocompatibility complex in germfree mice.

The major histocompatibility complex (MHC) is the prime but not exclusive determinant of genetically specific constitutive body odors, termed odor types, represented strongly in urine of the mouse. Perception of MHC-determined odor types influences reproductive behavior in the contexts of mate choice and maintenance of early pregnancy, tending to favor the propagation of one MHC type over another. How MHC genotype determines MHC odor type is unknown. One possible explanation is that differential odorants are generated by populations of commensal microorganisms whose composition is somehow geared to MHC diversity. This hypothesis was tested in the Y-maze system in which mice are trained to distinguish the urinary odors of MHC-congenic mice. First, it was shown that mice could readily be trained to distinguish the urines of germfree MHC-congenic mice. Second, it was shown that mice trained to distinguish the urines of conventionally maintained MHC-congenic mice could as readily distinguish the urines of germfree MHC-congenic mice. These results imply that MHC-determined odor types do not depend on odorants generated by microorganisms.

Animals↗
PubMed1992

Circulating estrogens in a male songbird originate in the brain.

Gonadal steroids act on brain to regulate the development and expression of vertebrate reproductive behavior. In addition, steroid targets in brain are an integral part of the feedback regulation of gonadal steroidogenesis. The actions of androgens in brain are often mediated by enzymatic activation or inactivation of circulating hormone, including local conversion of androgen to estrogen. We now report that in zebra finches, the brain synthesizes large quantities of estrogen from androgen and releases this estrogen into blood. Since there appears to be no other significant source of estrogen synthesis in adult male zebra finches, it is likely that the brain directly controls plasma levels of this steroid by contributing most or all of the high levels of estrogen found in the circulation.

Adrenal Glands↗
PubMed1992

Guanyl nucleotides modulate binding to steroid receptors in neuronal membranes.

The recently characterized corticosteroid receptor on amphibian neuronal membranes appears to mediate rapid, stress-induced changes in male reproductive behaviors. Because the transduction mechanisms associated with this receptor are unknown, we performed radioligand binding studies to determine whether this steroid receptor is negatively modulated by guanyl nucleotides. The binding of [3H]corticosterone to neuronal membranes was inhibited by nonhydrolyzable guanyl nucleotides in both equilibrium saturation binding and titration studies. The addition of guanyl nucleotide plus unlabeled corticosterone induced a rapid phase of [3H]corticosterone dissociation from membranes that was not induced by addition of unlabeled ligand alone. Furthermore, the equilibrium binding of [3H]corticosterone and the sensitivity of the receptor to modulation by guanyl nucleotides were both enhanced by Mg2+. These results are consistent with the formation of a ternary complex of steroid, receptor, and guanine nucleotide-binding protein that is subject to regulation by guanyl nucleotides. Therefore, rapid signal transduction through corticosteroid receptors on neuronal membranes appears to be mediated by guanine nucleotide-binding proteins.

Animals↗
PubMed1994

Discrimination of odortypes determined by the major histocompatibility complex among outbred mice.

Genetically determined body odors that distinguish one mouse from another are termed odortypes. The best known odortypes, highly expressed in urine, are those specified by H-2, the major histocompatibility complex of the mouse, but other odortypes originate from unidentified loci in the rest of the genome, including both sex chromosomes. The definition of H-2 odortypes and evidence that their perception affects reproductive behavior have so far depended on studies with inbred mouse strains whose genetic differences are confined to the H-2 complex of genes. To simulate feral conditions more closely, a freely segregating population was bred from crosses involving four unrelated inbred strains contributing four different H-2 haplotypes. After H-2 typing, this outbred population was divided into four groups of freely segregating mice, comprising the four distinct H-2 genotypes represented, to serve as conventional donors of urine for evaluation in the standard Y-maze system used in the training and testing of mice for H-2 odortype discrimination. With respect to utility in training mice for H-2 odortype discrimination, and to degrees of concordance attained in the Y-maze by trained mice, these urinary H-2 odortype sources from outbred mice were no less effective than urines customarily obtained for those purposes from nonsegregating inbred donors. We conclude that discrimination of H-2 odortypes is not appreciably affected or impaired by the usual concurrent segregation within the genome as a whole.

Animals↗
PubMed1995

Evidence suggesting that the odortypes of pregnant women are a compound of maternal and fetal odortypes.

Odortypes--namely, body odors that distinguish one individual from another on the basis of genetic polymorphism at the major histocompatibility complex and other loci--are a fundamental element in the social life and reproductive behavior of the mouse, including familial imprinting, mate choice, and control of early pregnancy. Odortypes are strongly represented in urine. During mouse pregnancy, an outcrossed mother's urine acquires fetal major histocompatibility complex odortypes of paternal origin, an observation that we took as the focus of a search for odortypes in humans, using a fully automated computer-programmed olfactometer in which trained rats are known to distinguish precisely the odortypes of another species. Five women provided urine samples before and after birth, which in each case appropriately trained rats were found to distinguish in the olfactometer. Whether this olfactory distinction of mothers' urine before and after birth reflects in part the odortype and hence genotype of the fetus, and not just the state of pregnancy per se, was tested in a second study in which each mother's postpartum urine was mixed either with urine from her own infant or with urine of a different, same-aged infant. Responses of trained rats were more positive with respect to the former (congruous) mixtures than to the latter (incongruous) mixtures, implying that, as in the mouse, human fetal odortypes of paternal genomic origin are represented in the odortype of the mother, doubtless by circulatory transfer of the pertinent odorants.

Animals↗
PubMed1999

Widespread accumulation of [(3)H]testosterone in the spinal cord of a wild bird with an elaborate courtship display.

Elaborate courtship displays are relatively common features of the masculine reproductive behavior in birds. However, little is known about their neural and hormonal control. One bird that performs such a display is the golden-collared manakin (Manacus vitellinus) of Panamanian forests. Adult males, but not females, perform a physically intense display requiring substantial neuromuscular control of the wings and legs. We tested the hypothesis that steroid sensitivity is a property of neurons in the manakin spinal cord. Males and females were captured from active courtship leks, treated with drugs to block steroidogenesis, injected with (3)H-labeled testosterone, and the spinal cords were removed and processed for autoradiography. Sex steroid-accumulating cells were widely distributed in the spinal cords in each of six males and in one of five females. Cells, including presumptive motoneurons, reached their highest density in the ventral horns of the cervical and lumbosacral enlargements, regions associated with motor control of the wings and legs. These results suggest that neurons in the adult manakin spinal cord can express sex-steroid receptors, but do so less in females than in males. This evidence for androgen sensitivity and sexual dimorphism in the adult avian spinal cord suggests that sex steroids may control diverse behaviors in male birds in part by acting directly on the spinal neural circuits.

Animals↗
PubMed1999

The 70-kDa heat shock cognate protein (Hsc73) gene is enhanced by ovarian hormones in the ventromedial hypothalamus.

Estrogen (E) and progesterone (P) orchestrate many cellular responses involved in female reproductive physiology, including reproductive behaviors. E- and P-binding neurons important for lordosis behavior have been located within the ventromedial hypothalamus (VMH), and several hormone-responsive genes have been observed there as well. In attempts to identify additional E- and P-responsive genes in the VMH that may contribute to sexual behaviors, we used the differential display mRNA screening technique. One of the genes identified encodes the 73-kDa heat shock cognate protein (Hsc73). Quantitative in situ hybridization analysis of brains from naturally cycling female rats revealed a significant increase in Hsc73 mRNA in the VMH and arcuate nucleus of animals during proestrus compared with those at diestrus-1. To confirm that these increases were steroid hormone dependent, we compared vehicle-treated ovariectomized females with ovariectomized females treated with estradiol benzoate and P. Northern analysis and in situ hybridizations showed that the Hsc73 gene is enhanced by E and P in the pituitary and subregions of the VMH. Incidentally, by examining the primary amino acid sequence of rat, human, and chicken progesterone receptors, we noticed that putative Hsc73 binding sites are conserved across species with similar sites existing in the androgen and glucocorticoid receptors. Together these findings suggest a possible mechanism through which E could influence the activities of progesterone, androgen, and glucocorticoid receptors, by enhancing the expression of Hsc73 in cells where these proteins colocalize.

Amino Acid Sequence↗
PubMed1997

Disruption of the gene encoding the mitogen-regulated translational modulator PHAS-I in mice.

PHAS-I is the prototype of a group of eIF4E-binding proteins that can regulate mRNA translation in response to hormones and growth factors. To investigate the importance of PHAS-I in the physiology of the intact animal, we disrupted the PHAS-I gene in mice. Tissues and cells derived from the knockout mice contained no detectable PHAS-I protein. A related protein, PHAS-II, and eIF4E were readily detectable in tissues from these animals, but neither appeared to be changed in a compensatory manner. Mice lacking PHAS-I appeared normal at birth. However, male knockout mice weighed approximately 10% less than controls at all ages, whereas female weights were similar to those of controls. Both males and females were fertile. Tissues from adult animals appeared to be normal by routine histological staining techniques, as were routine blood cell counts and chemistries. Fibroblasts derived from PHAS-I-deficient mouse embryos exhibited normal rates of growth and overall protein synthesis, responded normally to serum stimulation of ornithine decarboxylase activity and cell growth, and rapamycin inhibition of cell growth. Under these experimental conditions, PHAS-I is apparently not required for the normal development and reproductive behavior of female mice, but is required for normal body weight in male mice; the mechanisms responsible for this phenotype remain to be determined.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Selective activation of G protein subtypes in the vomeronasal organ upon stimulation with urine-derived compounds.

Chemosensory neurons in the vomeronasal organ (VNO) detect pheromones related to social and reproductive behavior in most terrestrial vertebrates. Current evidence indicate that the chemoelectrical transduction process is mediated by G protein-coupled second messenger cascades. In the present study, attempts were made to identify the G protein subtypes which are activated upon stimulation with urinary pheromonal components. G protein-specific antibodies were employed to interfere specifically with inositol 1,3,4-trisphosphate formation induced by urinary stimuli and to immunoprecipitate Galpha-subunits, activation dependently labeled with [alpha-32P]GTP azidoanilide. The results of both experimental approaches indicate that stimulation of female VNO membrane preparations with male urine samples induces activation of Gi as well as Go subtypes. Experiments using different fractions of urine revealed that upon stimulation with lipophilic volatile odorants, only Gi proteins were activated, whereas Go activation was elicited by alpha2u-globulin, a major urinary protein, which is a member of the lipocalin superfamily. Since each G protein subtype is stereotypically coexpressed with one of the two structurally different candidate pheromone receptors (V1R and V2R), the results provide the first experimental evidence that V1Rs coexpressed with Gi may be activated by lipophilic probably volatile odorants, whereas V2Rs coexpressed with Go seem to be specialized to interact with pheromonal components of proteinaceous nature.

Alpha-Globulins↗
PubMed1999

Evidence for conservation of the vasopressin/oxytocin superfamily in Annelida.

Annetocin is a structurally and functionally oxytocin-related peptide isolated from the earthworm Eisenia foetida. We present the characterization of the annetocin cDNA. Sequence analyses of the deduced precursor polypeptide revealed that the annetocin precursor is composed of three segments: a signal peptide, an annetocin sequence flanked by a Gly C-terminal amidation signal and a Lys-Arg dibasic processing site, and a neurophysin domain, similar to other oxytocin family precursors. The proannetocin showed 37.4-45.8% amino acid homology to other prohormones. In the neurophysin domain, 14 cysteines and amino acid residues essential for association of a neurophysin with a vasopressin/oxytocin superfamily peptide were conserved, suggesting that the Eisenia neurophysin can bind to annetocin. Furthermore, in situ hybridization experiments demonstrated that the annetocin gene is expressed exclusively in neurons of the central nervous system predicted to be involved in regulation of reproductive behavior. These findings confirm that annetocin is a member of the vasopressin/oxytocin superfamily. This is the first identification of the cDNA encoding the precursor of an invertebrate oxytocin-related peptide and also the first report of the identification of an annelid vasopressin/oxytocin-related precursor.

Amino Acid Sequence↗
PubMed2003

Human CLK2 links cell cycle progression, apoptosis, and telomere length regulation.

Mutations in the clk-2 gene of the nematode Caenorhabditis elegans affect organismal features such as development, behavior, reproduction, and aging as well as cellular features such as the cell cycle, apoptosis, the DNA replication checkpoint, and telomere length. clk-2 encodes a novel protein (CLK-2) with a unique homologue in each of the sequenced eukaryotic genomes. We have studied the human homologue of CLK-2 (hCLK2) to determine whether it affects the same set of cellular features as CLK-2. We find that overexpression of hCLK2 decreases cell cycle length and that inhibition of hCLK2 expression arrests the cell cycle reversibly. Overexpression of hCLK2, however, renders the cell hypersensitive to apoptosis triggered by oxidative stress or DNA replication block and gradually increases telomere length. The evolutionary conservation of the pattern of cellular functions affected by CLK-2 suggests that the function of hCLK2 in humans might also affect the same organismal features as in worms, including life span. Surprisingly, we find that hCLK2 is present in all cellular compartments and exists as a membrane-associated as well as a soluble form.

Apoptosis↗
PubMed2003

Identification and structural characterization of the neuronal luteinizing hormone receptor associated with sensory systems.

The luteinizing hormone receptor (LHR) is a G protein-coupled receptor involved in regulation of ovarian and testicular functions. Here we show that the receptor is present also in specific areas of the peripheral and central nervous system and may thus have a broader functional role than has been anticipated. Full-length LHR mRNA and two receptor protein species of M(r) 90,000 and 73,000, representing mature and precursor forms, respectively, were expressed in adult and developing rat nervous tissue, starting at fetal day 14.5. The receptor was capable of ligand binding because it was purified by ligand affinity chromatography, and human chorionic gonadotropin and LH were able to displace (125)I-labeled human chorionic gonadotropin binding to fetal head membranes in a dose-dependent manner. Finally, two 5'-flanking sequences ( approximately 2 and 4 kb) of the rat LHR gene were shown to direct expression of the lacZ reporter to specific areas of the peripheral and central nervous system in fetal and adult transgenic mice, especially to structures associated with sensory, memory, reproductive behavior, and autonomic functions. Importantly, the transgene activity was confined to neurons and colocalized with the cytochrome P450 side chain cleavage enzyme. Taken together, these results indicate that the neuronal LHR is a functional protein, implicating a role in neuronal development and function, possibly by means of regulating synthesis of neurosteroids.

Animals↗
PubMed2002

Selective G protein beta gamma-subunit compositions mediate phospholipase C activation in the vomeronasal organ.

Chemosensory neurons of the vomeronasal organ (VNO) are supposed to detect pheromones controlling social and reproductive behavior in most terrestrial vertebrates. Recent studies indicate that pheromone signaling in VNO neurons is mediated via phospholipase C (PLC) activation generating the two second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Since G alpha(i) and G alpha(o) predominantly expressed in VNO neurons are usually not involved in activating PLC, it was explored if PLC activation may be mediated by G beta gamma subunits. It was found that a scavenger for beta gamma dimers reduced the urine-induced IP3 formation in VNO preparations in a dose-dependent manner indicating a role for G beta gamma complexes. Towards an identification of the relevant G beta and G gamma subunit(s), PCR approaches as well as immunohistochemical experiments were performed. It was found that out of the five known G beta subtypes, only G beta2 was expressed in both G alpha(i) as well as G alpha(o) neurons. Experimental approaches focusing on the spatial expression profile of identified G gamma subtypes revealed that G gamma8-positive neurons are preferentially localized to the basal region of the vomeronasal epithelium, whereas G gamma2-reactive cells are restricted to the apical G alpha(i)-positive layer of the sensory epithelium. As IP3 formation induced upon stimulation with volatile urinary compounds was selectively blocked by G gamma2-specific antibodies whereas second messenger formation elicited upon stimulation with alpha2u globulin was inhibited by antibodies recognizing G gamma8, it is conceivable that PLC activation in the two populations of chemosensory VNO neurons is mediated by different G beta gamma complexes.

Animals↗
PubMed1985

Role of timing of visual monitoring and motor rehearsal in observational learning of action patterns.

This experiment tested the hypothesis that observational learning is enhanced by visual monitoring of enactments that is optimally timed for conception-action matching and by motor rehearsal that serves to refine the cognitive representation. Subjects observed a modeled action pattern, after which they enacted it with either concurrent, delayed, or no visual monitoring. They then engaged in motor rehearsal or did not rehearse the action pattern. Development of the cognitive representation of the modeled action was also measured. Concurrent visual monitoring of enactments greatly facilitated observational learning, whereas delayed visual monitoring did not affect the acquisition process. Rehearsal aided cognitive representation and behavioral reproduction. The more accurate the cognitive representation of the modeled action pattern, the more skilled were the subsequent reproductions of it. After gaining proficiency in converting conception to action, subjects showed no decline in reproduction accuracy when modeling and visual monitoring were withdrawn.

Journal Article↗
PubMed2005

Harming by conceiving: a review of misconceptions and a new analysis.

An objection often is raised against the use of reproductive technology to create "nontraditional families," as in ovum donation for postmenopausal women or postmortem artificial insemination. The objection states that conceiving children in such circumstances is harmful to them because of adverse features of these nontraditional families. A similar objection is raised when parents, through negligence or willful disregard of risks, create children with serious genetic diseases or other developmental handicaps. It is claimed that such reproduction harms the children who are created. In reply to this Harm to the Child Argument, it has been pointed out that the procreative acts that supposedly harm the child are the very acts that create the child. This reply has been developed into an argument that, in most of the types of cases under consideration, creating the child does not harm her. This reply, the No Harm Argument, has been stated in three main ways, and it is one of the most misunderstood arguments in bioethics. This paper examines the main rebuttals that have been made to the No Harm Argument and argues that none of them is successful.

Ethical Theory↗