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1.
Hannon RM Kelly SA Middleton KM Kolb EM Pomp D Garland T 《The Journal of heredity》2008,99(4):349-354
From outbred Hsd:ICR mice, we selectively bred 4 replicate lines for high running (High-Runner [HR] lines) on wheels while maintaining 4 nonselected lines as controls (C lines). An apparent Mendelian recessive, the "mini-muscle" (MM) allele, whose main phenotypic effect is to reduce hindlimb muscle mass by 50%, was discovered in 2 HR lines and 1 C line. This gene of major effect has gone to fixation in one selected line, remains polymorphic in another, and is now undetectable in the one C line. Homozygotes exhibit various pleiotropic effects, including a doubling of mass-specific muscle aerobic capacity, and larger hearts, livers, and spleens. To create a population suitable for mapping the genomic location of the MM allele and to better characterize its pleiotropic effects, we crossed females fixed for the MM allele with male C57BL/6J. F(1) males were then backcrossed to the MM parent females. Backcross (BC) mice (N = 404) were dissected, and a 50:50 ratio of normal to MM phenotype was observed with no overlap in relative muscle mass. In the BC, analysis of covariance revealed that MM individuals ran significantly more on days 5 and 6 of a 6-day exposure to running wheels (as in the routine selective-breeding protocol), were smaller in body mass, and had larger ventricles and spleens. 相似文献
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3.
Selective breeding as a tool to probe skeletal response to high voluntary locomotor activity in mice
We present a novel mouse-model for the study of skeletal structureand evolution, based on selective breeding for high levels ofvoluntary wheel running. Whereas traditional models (originallyinbred strains, more recently knockouts and transgenics) relyon the study of mutant or laboratory-manipulated phenotypes,we have studied changes in skeletal morphometrics resultingfrom many generations of artificial selection for high activityin the form of wheel running, in which mice engage voluntarily.Mice from the four replicate High Runner (HR) lines run nearlythree times as many revolutions during days 5 and 6 of a 6-dayexposure to wheels (1.12 m circumference). We have found significantchanges in skeletal dimensions of the hind limbs, includingdecreased directional asymmetry, larger femoral heads, and widerdistal femora. The latter two have been hypothesized as evolutionaryadaptations for long-distance locomotion in hominids. Exercise-trainingstudies involving experimental groups with and without accessto wheels have shown increased diameters of both femora andtibiafibulae, and suggest genetic effects on trainability (genotype-by-environmentinteractions). Reanalysis of previously published data on bonemasses of hind limbs revealed novel patterns of change in bonemass associated with access to wheels for 2 months. Withoutaccess to wheels, HR mice have significantly heavier tibiafibulaeand foot bones, whereas with chronic access to wheels, a significantincrease in foot bone mass that was linearly related to increasesin daily wheel running was observed. Mice exhibiting a recentlydiscovered small-muscle phenotype ("mini-muscle," [MM] causedby a Mendelian recessive gene), in which the mass of the tricepssurae muscle complex is 50% lower than in normal individuals,have significantly longer and thinner bones in the hind limb.We present new data for the ontogenetic development of musclemass in Control, HR, and MM phenotypes in mice of 1–7weeks postnatal age. Statistical comparisons reveal highly significantdifferences both in triceps surae mass and mass-corrected tricepssurae mass between normal and MM mice at all but the postnatalage of 1 week. Based on previously observed differences in distributionsof myosin isoforms in adult MM mice, we hypothesize that a reductionof myosin heavy-chain type-IIb isoforms with accounts for ourobserved ontogenetic changes in muscle mass. 相似文献
4.
Scott A. Kelly Timothy A. Bell Sara R. Selitsky Ryan J. Buus Kunjie Hua George M. Weinstock Theodore Garland Jr. Fernando Pardo-Manuel de Villena Daniel Pomp 《Genetics》2013,195(4):1385-1395
Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind-limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing ∼100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using high-density genotyping and whole-genome sequencing of key backcross individuals and HR mice with and without the mini-muscle mutation, from both recent and historical generations of the HR lines, we show that a SNP representing a C-to-T transition located in a 709-bp intron between exons 11 and 12 of the Myosin heavy polypeptide 4 (Myh4) skeletal muscle gene (position 67,244,850 on MMU11; assembly, December 2011, GRCm38/mm10; ENSMUSG00000057003) is responsible for the mini-muscle phenotype, Myh4Minimsc. Using next-generation sequencing, our approach can be extended to identify causative mutations arising in mouse inbred lines and thus offers a great avenue to overcome one of the most challenging steps in quantitative genetics. 相似文献
5.
Jacob DA Ray T Bengston CL Lindsten T Wu J Thompson CB Forger NG 《Developmental neurobiology》2008,68(11):1303-1314
The bulbocavernosus (BC) and levator ani (LA) muscles are present in males but absent or severely reduced in females, and the fate of these muscles controls the survival of motoneurons in the sexually dimorphic spinal nucleus of the bulbocavernosus. However, the mechanism underlying the sex difference in BC and LA development has been controversial. We examined the role of cell death in sexual differentiation of the bulbocavernosus BC/LA muscles in mice. Muscle development was mapped from embryonic day 16 (E16) to postnatal day 5 (P5). A sex difference (male>female) first arose on E17 (BC) or E18 (LA), and increased in magnitude postnatally. TUNEL labeling revealed dying cells in the BC and LA muscles of both sexes perinatally. However, females had a significantly higher density of TUNEL-positive cells than did males. A role for the proapoptotic factors, Bax and Bak, in BC/LA development was tested by examining mice lacking one or both of these proteins. In females lacking either Bax or Bak, the BC was absent and the LA rudimentary. Deletion of both bax and bak genes, however, rescued the BC, increased LA size approximately 20-fold relative to controls, and virtually eliminated TUNEL-positive cells in both muscles. We conclude that cell death plays an essential role in sexual differentiation of the BC/LA muscles. The presence of either Bax or Bak is sufficient for cell death in the BC/LA, whereas the absence of both prevents sexually dimorphic muscle cell death. 相似文献
6.
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. 相似文献
7.
Joong‐Jean Park Michelle Howell Adam Winseck Nancy G. Forger 《Developmental neurobiology》1999,41(3):317-325
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 α‐receptor (CNTFRα). To test the role of CNTFRα in the response of the developing SNB system to testosterone, CNTFRα +/+ 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 CNTFRα −/− 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 CNTFRα gene deletion on muscle size in males. However, the effect of TP treatment on BC and LA muscle sizes was blunted in CNTFRα −/− 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, CNTFRα knockout mice. Prenatal treatment with testosterone did not increase SNB motoneuron number in CNTFRα −/− 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 CNTFRα −/− mice. Moreover, the CNTFRα gene deletion influences perineal muscle development and the response of the perineal muscles to testosterone. Prenatal TP treatment of CNTFRα −/− males overcomes the effects of the gene deletion on the BC and LA muscles without a concomitant effect on SNB motoneuron number. © 1999 John Wiley & Sons, Inc. J Neurobiol 41: 317–325, 1999 相似文献
8.
Fangfang Wang Zhang Dan Hongmei Luo Jingcao Huang Yushan Cui Hong Ding Juan Xu Zhimei Lin Yuhan Gao Xinyu Zhai Yan Yang Ying Qu Li Zhang Fengjiao Chen Qiang Wang Xin Wang Yu Feng Ting Liu Qing Yi Ting Niu Yuhuan Zheng 《Cell death & disease》2022,13(2)
Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.Subject terms: Cancer microenvironment, RNAi 相似文献
9.
Mapping quantitative trait loci in inbred backcross lines of Lycopersicon pimpinellifolium (LA1589). 总被引:3,自引:0,他引:3
Although tomato has been the subject of extensive quantitative trait loci (QTLs) mapping experiments, most of this work has been conducted on transient populations (e.g., F2 or backcross) and few homozygous, permanent mapping populations are available. To help remedy this situation, we have developed a set of inbred backcross lines (IBLs) from the interspecific cross between Lycopersicon esculentum cv. E6203 and L. pimpinellifolium (LA1589). A total of 170 BC2F1 plants were selfed for five generations to create a set of homozygous BC2F6 lines by single-seed descent. These lines were then genotyped for 127 marker loci covering the entire tomato genome. These IBLs were evaluated for 22 quantitative traits. In all, 71 significant QTLs were identified, 15% (11/71) of which mapped to the same chromosomal positions as QTLs identified in earlier studies using the same cross. For 48% (34/71) of the detected QTLs, the wild allele was associated with improved agronomic performance. A number of new QTLs were identified including several of significant agronomic importance for tomato production: fruit shape, firmness, fruit color, scar size, seed and flower number, leaf curliness, plant growth, fertility, and flowering time. To improve the utility of the IBL population, a subset of 100 lines giving the most uniform genome coverage and map resolution was selected using a randomized greedy algorithm as implemented in the software package MapPop (http://www.bio.unc.edu/faculty/vision/lab/ mappop/). The map, phenotypic data, and seeds for the IBL population are publicly available (http://soldb.cit.cornell.edu) and will provide tomato geneticists and breeders with a genetic resource for mapping, gene discovery, and breeding. 相似文献
10.
Alfadda A DosSantos RA Stepanyan Z Marrif H Silva JE 《American journal of physiology. Regulatory, integrative and comparative physiology》2004,287(1):R147-R156
To define the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPD; EC 1.1.99.5) in energy balance and intermediary metabolism, we studied transgenic mice not expressing mGPD (mGPD-/-). These mice had approximately 14% lower blood glucose; approximately 50% higher serum glycerol; approximately 80% higher serum triglycerides; and at thermoneutrality, their energy expenditure (Qo(2)) was 15% lower than in wild-type (WT) mice. Glycerol-3-phosphate levels and lactate-to-pyruvate ratios were threefold elevated in muscle, but not in liver, of mGPD-/- mice. WT and mGPD-/- mice were then challenged with a high-fat diet, fasting, or food restriction. The high-fat diet caused more weight gain and adiposity in mGPD-/- than in WT female mice, without the genotype differentially affecting Qo(2) or energy intake. After a 30-h fast, WT female lost 60% more weight than mGPD-/- mice but these latter became more hypothermic. When energy intake was restricted to 50-70% of the ad libitum intake for 10 days, mGPD-/- female mice lost less weight than WT controls, but they had lower Qo(2) and body temperature. WT and mGPD-/- male mice did not differ significantly in their responses to these challenges. These results show that the lack of mGPD causes significant alterations of intermediary metabolism, which are more pronounced in muscle than liver and lead to a thrifty phenotype that is more marked in females than males. Lower T(4)-to-T(3) conversion in mGPD-/- females and a greater reliance of normal females on mGPD to respond to high-fat diets make the lack of the enzyme more consequential in the female gender. 相似文献
11.
We modified an existing model for European corn borer, Ostrinia nubilalis (Hübner) (Lepidoptera: Crambidae), population dynamics and genetics to evaluate the effectiveness of oviposition deterrence in transgenic fields for resistance management. We simulated two types of deterrence: one type has females reducing their oviposition because of lost opportunities to lay eggs (eggs lost), and the other type has the deterred females moving to the refuge to lay eggs. Oviposition deterrence was clearly effective in extending the time to resistance to transgenic corn (R allele) in the European corn borer, particularly when 80% or more of the eggs were deterred from being oviposited on the transgenic plants. With 90% of eggs deterred, the time required to reach 50% R-allele frequency increases 3.7- to 5.5-fold compared with the no-deterrence scenario. The time to 50% R-allele frequency was similar for the two types of simulated deterrence, but the densities of the European corn borer were 100-fold higher when the deterred females oviposited in the refuge. The Y allele for insensitivity or resistance to deterrence never reached 50% within the 50-yr time line for these simulations except when the R allele was dominant and the Y allele was not recessive. The time to 50% Y-allele frequency was 33 and 26 yr when the Y allele was additive or dominant, respectively, when 50% of the eggs were deterred, but the time decreased to 18 and 16 yr when 90% of the eggs were deterred. The effectiveness of oviposition deterrence on time to resistance to transgenic insecticidal plants was not changed much when we altered our assumptions about behavior in a sensitivity analysis. 相似文献
12.
Cell surface fibroblast growth factor and epidermal growth factor receptors are permanently lost during skeletal muscle terminal differentiation in culture 总被引:19,自引:7,他引:12
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One characteristic of skeletal muscle differentiation is the conversion of proliferating cells to a population that is irreversibly postmitotic. This developmental change can be induced in vitro by depriving the cultures of specific mitogens such as fibroblast growth factor (FGF). Analysis of cell surface FGF receptor (FGFR) in several adult mouse muscle cell lines and epidermal growth factor receptor (EGFR) in mouse MM14 cells reveals a correlation between receptor loss and the acquisition of a postmitotic phenotype. Quiescent MM14 cells, mitogen-depleted, differentiation-defective MM14 cells, and differentiated BC3H1 muscle cells (a line that fails to become postmitotic upon differentiation) retained their cell surface FGFR. These results indicate that FGFR loss is not associated with either reversible cessation of muscle cell proliferation or biochemical differentiation and thus, further support a correlation between receptor loss and acquisition of a postmitotic phenotype. Comparison of the kinetics for growth factor receptor loss and for commitment of MM14 cells to a postmitotic phenotype reveals that FGFR rises transiently from approximately 700 receptors/cell to a maximum of approximately 2,000 receptors/cell 12 h after FGF removal, when at the same time, greater than 95% of the cells are postmitotic. FGFR levels then decline to undetectable levels by 24 h after FGF removal. During the interval in which FGFR increases and then disappears there is no change in its affinity for FGF. The transient increase in growth factor receptors appears to be due to a decrease in ligand-mediated internalization because EGFR, which undergoes an immediate decline when cultures are deprived of FGF (Lim, R. W., and S. D. Hauschka. 1984. J. Cell Biol. 98:739-747), exhibits a similar transient rise when cultures are grown in media containing both EGF and FGF before switching the cells to media without these added factors. These results indicate that the loss of certain growth factor receptors is a specific phenotype acquired during skeletal muscle differentiation, but they do not resolve whether regulation of FGFR number is causal for initiation of the postmitotic phenotype. A general model is presented in the discussion. 相似文献
13.
In rats, motoneurons of the spinal nucleus of the bulbocavernosus (SNB) innervate the bulbocavernosus (BC) muscle, which surrounds the base of the penis. The SNB/BC is a sexually dimorphic, steroid-sensitive neuromuscular system, which is critically important in male reproductive behavior. Androgens are necessary for the development, morphology, and function of the SNB/BC system. However, estradiol (E) is also necessary for the development of the SNB/BC system, and E is capable of maintaining BC EMG activity in adulthood. In this study, we used electrophysiological and anatomical methods to examine estrogenic effects on BC EMG activity. We used a modified H-reflex testing method to investigate polysynaptic reflex characteristics in intact males, castrates, and castrates treated short term with estradiol benzoate (EB). Measures of EMG activity, response latency, and spike count were altered in castrates, but maintained in EB-treated castrates to the levels of intact males. Furthermore, estrogenic effects were found in EMG activity that could be isolated to the periphery of the SNB/BC system. BC NMJ size and muscle fiber area have been demonstrated to be hormone sensitive, and we examined these for possible correlates of E's effects on BC EMG activity. BC muscles of intact males, castrates, and short-term EB-treated castrates were fixed and stained with zinc iodide and osmium tetroxide. NMJ size and muscle fiber area did not differ between groups. Together, these data suggest that E treatment results in changes in the neuromuscular periphery that maintain BC EMG activity, but this effect cannot be accounted for by changes in NMJ size or muscle fiber area. 相似文献
14.
Chromosomal locations and gonadal dependence of genes that mediate resistance to ectromelia (mousepox) virus-induced mortality. 总被引:5,自引:3,他引:2
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Four genetic loci were tested for linkage with loci that control genetic resistance to lethal ectromelia virus infection in mice. Three of the loci were selected because of concordance with genotypes assigned to recombinant inbred (RI) strains of mice derived from resistant C57BL/6 and susceptible DBA/2 (BXD) mice on the basis of their responses to challenge infection. Thirty-six of 167 male (C57BL/6 x DBA/2)F1 x DBA/2 backcross (BC) mice died (22%), of which 27 (75%) were homozygous for DBA/2 alleles at Hc and H-2D. Twenty-eight percent of sham-castrated and 6% of sham-ovariectomized BC mice were susceptible to lethal mousepox, whereas 50% of gonadectomized mice were susceptible. There was no linkage evident between Hc or H-2D and loci that controlled resistance to lethal ectromelia virus infection in 44 castrated BC mice. Mortality among female mice of BXD RI strains with susceptible or intermediate male phenotypes was strongly correlated (r = 0.834) with male mortality. Gonadectomized C57BL/6 mice were as resistant as intact mice to lethal ectromelia virus infection. These results indicate that two gonad-dependent genes on chromosomes 2 and 17 and one gonad-independent gene control resistance to mousepox virus infection, that males and females share gonad-dependent genes, and that the gonad-independent gene is fully protective. 相似文献
15.
As a dense map of single nucleotide polymorphism (SNP) markers are available, population-based linkage disequilibrium (LD) mapping or association study is becoming one of the major tools for identifying quantitative trait loci (QTL) and for fine gene mapping. However, in many cases, LD between the marker and trait locus is not very strong. Approaches that maximize the potential of detecting LD will be essential for the success of LD mapping of QTL. In this paper, we propose two strategies for increasing the probability of detecting LD: (1) phenotypic selection and (2) haplotype LD mapping. To provide the foundations for LD mapping of QTL under selection, we develop analytic tools for assessing the impact of phenotypic selection on allele and haplotype frequencies, and LD under three trait models: single trait locus, two unlinked trait loci, and two linked trait loci with or without epistasis. In addition to a traditional chi(2) test, which compares the difference in allele or haplotype frequencies in the selected sample and population sample, we present multiple regression methods for LD mapping of QTL, and investigate which methods are effective in employing phenotypic selection for QTL mapping. We also develop a statistical framework for investigating and comparing the power of the single marker and multilocus haplotype test for LD mapping of QTL. Finally, the proposed methods are applied to mapping QTL influencing variation in systolic blood pressure in an isolated Chinese population. 相似文献
16.
Jiang R Wang S Takahashi K Fujita H Fruci CR Breyer MD Harris RC Takahashi T 《Genesis (New York, N.Y. : 2000)》2012,50(9):685-692
Mice with endothelial nitric oxide synthase (eNOS) deletions have defined the crucial role of eNOS in vascular development, homeostasis, and pathology. However, cell specific eNOS function has not been determined, although an important role of eNOS has been suggested in multiple cell types. Here, we have generated a floxed eNOS allele in which exons 9–12, encoding the sites essential to eNOS activity, are flanked with loxP sites. Mice homozygous for the floxed allele showed normal eNOS protein levels and no overt phenotype. Conversely, homozygous mice with Cre‐deleted alleles displayed truncated eNOS protein, lack of vascular NO production, and exhibited similar phenotype to eNOS knockout mice, including hypertension, low heart rate, and focal renal scarring. These findings demonstrate that the floxed allele is normal and it can be converted to a non‐functional eNOS allele through Cre recombination. This mouse will allow time‐ and cell‐specific eNOS deletion. genesis 50:685–692, 2012. © 2012 Wiley Periodicals, Inc. 相似文献
17.
Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function
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Laustsen PG Russell SJ Cui L Entingh-Pearsall A Holzenberger M Liao R Kahn CR 《Molecular and cellular biology》2007,27(5):1649-1664
Cardiovascular disease is the leading cause of death in people with type 2 diabetes and is linked to insulin resistance even in the absence of diabetes. Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. By contrast, mice lacking the IGF-1 receptor or the IGF-1 receptor plus one Ir allele appear normal. Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function. 相似文献
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19.
The bulbocavernosus (BC) and levator ani (LA) muscles of rats show remarkable androgen-dependent sexual dimorphism. These muscles are additionally of interest because they are thought to indirectly mediate sexual differentiation of innervating spinal motoneurons. This sexual differentiation of the BC/LA is thought to be due to an increase in muscle units in the male rat during the first week after birth. We examined the cellular basis of this differentiation by studying satellite cells in the LA of postnatal day 2.5 rats, when sexual dimorphism is already prominent. Two experiments were performed in which LA satellite cells were measured: (1) wild-type (WT) males were compared with females and to Tfm androgen receptor mutant males, which are androgen insensitive despite producing masculine amounts of testosterone, and (2) females treated prenatally and/or postnatally with testosterone proprionate were compared with females receiving vehicle injections. Our results indicate that WT males have a larger LA and a greater number of satellite cells in the LA muscle than females or Tfm males. However, satellite cell density was similar for all three groups. Prenatal testosterone treatment masculinized LA size and resulted in a corresponding increase in satellite cell populations, while postnatal TP treatment resulted in a tendency for increased satellite cell density without a significant increase in LA size. Taken together, these studies indicate that satellite cells in the neonatal LA muscle are sexually dimorphic, and that this dimorphism likely results from perinatal actions of androgens on androgen receptors. 相似文献
20.
Quantitative trait locus (QTL) mapping can be accomplished through the method of selective genotyping, which is based on the differences of frequencies between an upper sample and a lower sample in population. However, amplifying the differences in marker allele frequencies in extreme samples may increase the probability for QTL mapping. Shannon entropy, which is a nonlinear function of allele frequencies, can be used to amplify the differences in marker allele frequencies. In this paper, we present a novel measure for linkage disequilibrium (LD) between a marker and single QTL, that is based on the comparison of the entropy and conditional entropy in a marker in extreme samples of population. This measure of LD between the marker and the trait locus can be used when the marker allele frequencies are known in the extreme samples of a population. We investigate the mapping performance in both analytic and simulation scenarios of a single QTL linked to a single marker. Our results show that the measure has very reasonable performance. In addition, a simulation study is performed on the basis of the haplotype frequencies of 10 SNPs of angiotensin-I converting enzyme (ACE) genes. 相似文献