| 1. |
- Aucott, Rebecca, et al.
(författare)
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HP1-beta is required for development of the cerebral neocortex and neuromuscular junctions
- 2008
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 183:4, s. 597-606
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Tidskriftsartikel (refereegranskat)abstract
- HP1 proteins are thought to be modulators of chromatin organization in all mammals, yet their exact physiological function remains unknown. In a first attempt to elucidate the function of these proteins in vivo, we disrupted the murine Cbx1 gene, which encodes the HP1-beta isotype, and show that the Cbx1(-/-) null mutation leads to perinatal lethality. The newborn mice succumbed to acute respiratory failure, whose likely cause is the defective development of neuromuscular junctions within the endplate of the diaphragm. We also observe aberrant cerebral cortex development in Cbx1(-/-) mutant brains, which have reduced proliferation of neuronal precursors, widespread cell death, and edema. In vitro cultures of neurospheres from Cbx1(-/-) mutant brains reveal a dramatic genomic instability. Our results demonstrate that HP1 proteins are not functionally redundant and that they are likely to regulate lineage-specific changes in heterochromatin organization.
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| 2. |
- Aydin, Ebru, et al.
(författare)
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A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects
- 2015
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Ingår i: Journal of Biosciences. - : Springer Science and Business Media LLC. - 0250-5991 .- 0973-7138. ; 40:2, s. 325-338
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Tidskriftsartikel (refereegranskat)abstract
- Mammals have three HP1 protein isotypes HP1 beta (CBX1), HPl gamma (CBX3) and HP1 alpha (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3(hypo)) causes a severe postnatal mortality with around 99% of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3(hypo/hypo) conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3(hypo/hypo) placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3(hypo/hypo) placental labyrinth are narrower than wild-type. Newborn Cbx3(hypo/hypo) pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for non-shivering themogenesis. We suggest that it is the small size of the ChX3(hypo/hypo) neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality.
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| 3. |
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| 4. |
- Brunner, Sandra, et al.
(författare)
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Overexpression of RPGR leads to male infertility in mice due to defects in flagellar assembly
- 2008
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Ingår i: Biology of Reproduction. - : Oxford University Press (OUP). - 0006-3363 .- 1529-7268. ; 79:4, s. 608-617
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Tidskriftsartikel (refereegranskat)abstract
- Male infertility is one possible consequence of a group of disorders arising from dysfunction of cilia. Ciliopathies include primary ciliary dyskinesia, polycystic kidney disease, Usher syndrome, nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome as well as some forms of retinal degenerations. Mutations in the retinitis pigmentosa GTPase regulator gene (RPGR) are best known for leading to retinal degeneration but have also been associated with ciliary dysfunctions affecting other tissues. To further study the involvement of RPGR in ciliopathies, transgenic mouse lines overexpressing RPGR were generated. Animals carrying the transgene in varying copy numbers were investigated. We found that infertility due to aberrant spermatozoa correlated with increased copy numbers. In animals with moderately increased gene copies of Rpgr, structural disorganization in the flagellar midpiece, outer dense fibers, and fibrous sheath was apparent. In contrast, in animals with high copy numbers, condensed sperm heads were present, but the flagellum was absent in the vast majority of spermatozoa, although early steps of flagellar biogenesis were observed. This complexity of defects in flagellar assembly suggests a role of RPGR in intraflagellar transport processes.
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| 5. |
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| 6. |
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| 7. |
- Cross, JC, et al.
(författare)
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Genes and development : a workshop report
- 2004
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Ingår i: Placenta Supplement A, Trophoblast Research. - : Elsevier BV. - 0143-4004. ; 18, s. S39-S41
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Tidskriftsartikel (refereegranskat)
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| 8. |
- Göndör, Anita, 1977-
(författare)
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Epigenetic Regulation of Higher Order Chromatin Conformations and Gene Transcription
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epigenetic states constitute heritable features of the chromatin to regulate when, where and how genes are expressed in the developing conceptus. A special case of epigenetic regulation, genomic imprinting, is defined as parent of origin-dependent monoallelic expression. The Igf2-H19 locus is considered as paradigm of genomic imprinting with a growth-promoting gene, Igf2, expressed paternally and a growth antagonist, H19 encoding a non-coding transcript, expressed only from the maternal allele. The monoallelic expression patterns are regulated by the epigenetic status at an imprinting control region (ICR) in the 5´-flank of the H19 gene. The chromatin insulator protein CTCF interacts with only the maternal H19 ICR allele to prevent downstream enhancers to communicate with the Igf2 promoters. Mutations of these CTCF binding sites lead to biallelic Igf2 expression, increased size of the conceptus and predisposition for cancer. Reasoning that these effects cannot be explained by the regulation of Igf2 expression alone, a technique was invented to examine long-range chromatin interactions without prior knowledge of the interacting partners. Applying the circular chromosomal conformation capture (4C) technique to mouse neonatal liver cells, it was observed that 114 unique sequences interacted with the H19 ICR. A majority of these interactors was in complex with only the maternal H19 ICR allele and depended on the presence of functional CTCF binding sites. The functional consequence of chromosomal networks was demonstrated by the observation that the maternal H19 ICR allele regulated the transcription of two genes on another chromosome. As the chromosomal networks underwent reprogramming during the maturation of embryonic stem cells, attention was turned to human cancer cells, displaying features common with mouse embryonic stem cells. Subsequently, chromatin folding at the human H19 ICR suggested that stable chromatin loops were organized by synergistic interactions within and between baits and interactors. The presence of these interactions was linked to DNA methylation patterns involving repeat elements. A "flower" model of chromatin networks was formulated to explain these observations. This thesis has unravealed a novel feature of the epigenome and its functions to regulate gene expression in trans. The identified roles for CTCF as an architectural factor in the organization of higher order chromatin conformations may be of importance in understanding development and disease ontogeny from novel perspectives.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Kemkemer, Claus, et al.
(författare)
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Enrichment of brain-related genes on the mammalian X chromosome is ancient and predates the divergence of synapsid and sauropsid lineages
- 2009
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Ingår i: Chromosome Research. - : Springer Science and Business Media LLC. - 0967-3849 .- 1573-6849. ; 17:6, s. 811-820
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have revealed an enrichment of reproduction- and brain-related genes on the human X chromosome. In the present study, we investigated the evolutionary history that underlies this functional specialization. To do so, we analyzed the orthologous building blocks of the mammalian X chromosome in the chicken genome. We used Affymetrix chicken genome microarrays to determine tissue-selective gene expression in several tissues of the chicken, including testis and brain. Subsequently, chromosomal distribution of genes with tissue-selective expression was determined. These analyzes provided several new findings. Firstly, they showed that chicken chromosomes orthologous to the mammalian X chromosome exhibited an increased concentration of genes expressed selectively in brain. More specifically, the highest concentration of brain-selectively expressed genes was found on chicken chromosome GGA12, which shows orthology to the X chromosomal regions with the highest enrichment of non-syndromic X-linked mental retardation (MRX) genes. Secondly, and in contrast to the first finding, no enrichment of testis-selective genes could be detected on these chicken chromosomes. These findings indicate that the accumulation of brain-related genes on the prospective mammalian X chromosome antedates the divergence of sauropsid and synapsid lineages 315 million years ago, whereas the accumulation of testis-related genes on the mammalian X chromosome is more recent and due to adaptational changes.
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| 13. |
- Kourmouli, Niki, et al.
(författare)
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Heterochromatin and tri-methylated lysine 20 of histone H4 in animals
- 2004
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 117:14, s. 2491-2501
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Tidskriftsartikel (refereegranskat)abstract
- Tri-methylated lysine 20 on histone H4 (Me(3)K20H4) is a marker of constitutive heterochromatin in murine interphase and metaphase cells. Heterochromatin marked by Me(3)K20H4 replicates late during S phase of the cell cycle. Serum starvation increases the number of cells that exhibit high levels of Me(3)K20H4 at constitutive heterochromatin. Me(3)K20H4 is also present at the centromeric heterochromatin of most meiotic chromosomes during spermatogenesis and at the pseudoautosomal region, as well as at some telomeres. It is not present on the XY-body. During murine embryogenesis the maternal pronucleus contains Me(3)K20H4; Me(3)K20H4 is absent from the paternal pronucleus. On Drosophila polytene chromosomes Me(3)K20H4 is present in a `punctate pattern' at many chromosomal bands, including the chromocenter. In coccids it is present on the facultatively heterochromatinised paternal chromosome set. We also present evidence that Me(3)K20H4 is dependent upon H3-specific Suv(3)9 histone methyltransferase activity, suggesting that there may be `epigenetic cross-talk' between histones H3 and H4.
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| 14. |
- Looman, Camilla, et al.
(författare)
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An activating mutation in the PDGF receptor-beta causes abnormal morphology in the mouse placenta
- 2007
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Ingår i: International Journal of Developmental Biology. - : UPV/EHU Press. - 0214-6282 .- 1696-3547. ; 51:5, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- An oncogenic D842V mutation in the platelet-derived growth factor (PDGF) alpha-receptor (Pdgfra) has recently been described in patients with gastrointestinal stromal tumors. In order to test if the same mutation would confer oncogenic properties to the homologous PDGF beta-receptor (Pdgfrb), the corresponding aspartic acid residue at position 849 of Pdgfrb was changed into valine (D849V) using a knock-in strategy. This mutation turned out to be dominantly lethal and caused death even in chimeras (from 345 transferred chimeric blastocysts, no living coat chimeras were detected). Experiments employing mouse embryonic fibroblasts (MEFs) indicated hyperactivity of the mutant receptor. The mutant receptor was phosphorylated in a ligand-independent manner and, in contrast to wild-type MEFs, mutant cells proliferated even in the absence of ligand. Knockout experiments have previously indicated a role for Pdgfrb in placental development. We therefore analyzed wild-type and Pdgfrb D849V chimeric placentas from different gestational stages. No differences were detected at embryonic days 11.5 and 13.5 (n=4). At embryonic day 17.5, however, chimeric placentas (n=3/4) displayed abnormalities both in the labyrinth and in the chorionic plate. The changes included hyper-proliferation of alpha-smooth muscle actin and platelet/endothelial cell adhesion molecule-1 positive cells in the labyrinth and cells in the chorionic plate. In addition, the fetal blood vessel compartment of the labyrinth was completely disorganized.
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| 15. |
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| 16. |
- Meunier, Dominique, et al.
(författare)
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Expression Analysis of Proline Rich 15 (Prr15) in Mouse and Human Gastrointestinal Tumors
- 2011
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 50:1, s. 8-15
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Tidskriftsartikel (refereegranskat)abstract
- Proline rich 15 (Prr15), which encodes a protein of unknown function, is expressed almost exclusively in postmitotic cells both during fetal development and in adult tissues, such as the intestinal epithelium and the testis. To determine if this specific expression is lost in intestinal neoplasias, we examined Prr15 expression by in situ hybridization (ISH) on mouse intestinal tumors caused by different gene mutations, and on human colorectal cancer (CRC) samples. Prr15/PRR15 expression was consistently observed in mouse gastrointestinal (GI) tumors caused by mutations in the Apc gene, as well as in several advanced stage human CRCs. In contrast, no Prr15 expression was detected in intestinal tumors derived from mice carrying mutations in the Smad3, Smad4, or Cdkn1b genes. These findings, combined with the fact that a majority of sporadic human CRCs carry APC mutations, strongly suggest that the expression of Prr15/PRR15 in mouse and human GI tumors is linked, directly or indirectly, to the absence of the APC protein or, more generally, to the disruption of the Wnt signaling pathway.
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| 17. |
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| 18. |
- Samsioe, Annika, et al.
(författare)
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Intrauterine death, fetal malformation, and delayed pregnancy in Ljungan virus-infected mice
- 2006
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Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology. - : Wiley. - 1542-9733 .- 1542-9741. ; 77:4, s. 251-256
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A picornavirus (Ljunganvirus [LV]) has recently been associated with disease during pregnancy in its natural rodent reservoir and in humans. A study of laboratory mice infected under controlled conditions was therefore undertaken. METHODS: CD-1 female mice were infected gestational day two and subjected to varying regimes of stress. RESULTS: LV infection in combination with stress resulted in uterine resorptions, malformations, and neonatal death. A short delay in time to first pregnancy and births was observed in pairs infected in utero. CONCLUSIONS: LV is found in different species of native animals in both Europe and the United States and human epidemiological evidence connects LV and human reproduction, while the observations here indicate that LV is responsible for reproductive problems in a laboratory mouse model. The current findings suggest that the hypothesis that LV also causes disease in pregnant women and their offspring deserves further study.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Shi, Wei, 1970-
(författare)
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Growth and Behaviour : Epigenetic and Genetic Factors Involved in Hybrid Dysgenesis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In mammals, the most frequently observed hybrid dysgenesis effects are growth disturbances and male sterility. Profound defects in placental development have been described and our work on hybrids in genus Mus has demonstrated putative hybrid dysgenesis effects that lead to defects in lipid homeostasis and maternal behavior. Interestingly, mammalian interspecies hybrids exhibit strong parent-of-origin effects in that offspring of reciprocal matings, even though genetically identical, frequently exhibit reciprocal phenotypes. Recent studies have provided strong link between epigenetic regulation and growth, behavior and placental development. Widespread disruption of genomic imprinting has been described in hybrids between closely related species of the genus Peromyscus. The studies presented in this thesis aim to investigate the effects of disrupted epigenetics states on altered growth, female infanticide and placental dysplasia observed in Mus hybrids. We showed that loss-of-imprinting (LOI) of a paternally expressed gene, Peg1, was correlated with increased body weight of F1 hybrids. Furthermore, we investigated whether LOI of Peg1 in F1 females would interfere with maternal behavior. A subset of F1 females indeed exhibited highly abnormal maternal behavior in that they rapidly attacked and killed the pups. By microarray hybridization, a large number of differentially expressed genes in the infanticidal females as compared to normally behaving females were identified. In addtion to Peg1 LOI, we studied allelic expression of numerous imprinted genes in adult Mus interspecies hybrids. In contrast to the study from Peromyscus, patterns of LOI were not consistent with a direct influence of altered expression levels of imprinted genes on growth. Finally, we investigated the allelic interaction between an X-linked locus and a paternally expressed gene, Peg3, in placental defects in Mus hybrids. This study further strengthened the notion that divergent genetic and epigenetic mechanisms may be involved in hybrid dysgenesis in diverse groups of mammals.
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| 23. |
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| 24. |
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| 25. |
- Singh, Umashankar, et al.
(författare)
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Carboxypeptidase E in the mouse placenta
- 2006
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Ingår i: Differentiation. - : Elsevier BV. - 0301-4681 .- 1432-0436. ; 74:9-10, s. 648-660
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Tidskriftsartikel (refereegranskat)abstract
- Carboxypeptidase E (CPE) has important functions in processing of endocrine pro-peptides, such as pro-insulin, pro-opiomelanocortin, or pro-gonadotropin-releasing hormone, as evidenced by the hyperpro-insulinemia, obesity, and sterility of Cpe mutant mice. Down-regulation of Cpe in enlarged placentas of interspecific hybrid (interspecies hybrid placental dysplasia (IHPD)) and cloned mice suggested that reduced CPE enzyme and receptor activity could underlie abnormal placental phenotypes. In this study, we have explored the role of Cpe in murine placentation by determining its expression at various stages of gestation, and by phenotypic analysis of Cpe mutant placentas. Our results show that Cpe and Carboxypeptidase D (Cpd), another carboxypeptidase with a very similar function, are strictly co-localized in the mouse placenta from late mid-gestation to term. We also show that absence of CPE causes a sporadic but striking placental phenotype characterized by an increase in giant and glycogen cell numbers and giant cell hypertrophy. Microarray-based transcriptional pro. ling of Cpe mutant placentas identified only a very small number of genes with altered expression, including Dtprp, which belongs to the prolactin gene family. Concordant deregulation of Cpe and Cpd in abnormal placentas of interspecies hybrids before the onset of IHPD phenotype and recapitulation of some phenotypes of IHPD hyperplastic placentas in Cpe mutant placentas suggests that these two genes are causally involved in IHPD and may function as speciation genes in the genus Mus.
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| 26. |
- Singh, Umashankar, et al.
(författare)
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Characterization of a novel obesity phenotype caused by interspecific hybridization.
- 2008
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Ingår i: Archives of Physiology and Biochemistry. - : Informa UK Limited. - 1381-3455 .- 1744-4160. ; 114:5, s. 301-330
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Tidskriftsartikel (refereegranskat)abstract
- Interspecific hybridization in mammals causes hybrid dysgenesis effects, such as sterility and abnormal placentation. Here, we describe a novel obesity syndrome caused by interspecific hybridization in the genus Mus and show that this obesity, appearing sporadically in F1 littermates derived from inbred strains, has an epigenetic basis. Mus hybrids from various strains of M. musculus and M. spretus were generated and the sporadic obese phenotype was confirmed through assessment of physiological and biochemical parameters in littermates. To understand the underlying mechanisms, large-scale and candidate gene expression assays, global DNA methylation assays and allelic expression analysis were performed. Studies showed that obese hybrids are similar to other known models of obesity. While increased axial growth indicated a defect in POMC pathway, comparison of global gene expression patterns in brain of obese F1 and obese Pomc mutant mice showed little similarity. In F1 obese mice many genes involved in the maintenance of epigenetic states, as well as several imprinted genes, were differentially expressed. Global DNA methylation analysis in brain showed that increased methylation levels were associated with obesity. The imprinted gene Gnasxl, known to be important in lipid homeostasis, was found over expressed in the obese hybrids. Allelic expression and methylation analysis of Gnasxl showed that alterations of epigenetic marks underlying F1 obesity are probably many and multi-factorial. CONCLUSIONS: This model of obesity, which is both spontaneous and epigenetic, may be a useful tool to address the epigenetic aspects of clinical obesity.
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| 27. |
- Singh, Umashankar, et al.
(författare)
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Expression and Function of the Gene Encoding the Voltage-Dependent Calcium Channel β3-Subunit in the Mouse Placenta
- 2007
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Ingår i: Placenta. - : Elsevier BV. - 0143-4004 .- 1532-3102. ; 28:5-6, s. 412-420
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Tidskriftsartikel (refereegranskat)abstract
- Voltage-dependent Ca(2+) channels (VDCC) exist in most excitable cells and their properly regulated activity is essential for critical biological processes as many of these are sensitive to cellular Ca(2+) ion concentration. The ancillary cytoplasmic Ca(2+) channel beta subunits (CACNB) modulate Ca(2+) channel function and are required to enhance the number of functional channels in the plasma membrane. There are four genes encoding CACNB subunits and the gene encoding CACNB3 is over expressed in hyperplastic placentas of mouse interspecies hybrids. To determine the role of CACNB3 in the mouse placenta, we performed an expression and function analysis. Our results show that Cacnb3 exhibits specific spatial and temporal expression in the mouse placenta. Deletion of Cacnb3 does not produce a strong placental phenotype, which may be due to expression of other CACNB subunit encoding genes; however, sporadic occurrence of a labyrinthine architecture phenotype, characterized by reduced density of fetal blood vessels and decrease in pericyte number, could be observed. Down-regulation of Cacnb3 expression did not rescue placental hyperplasia in a model of interspecies hybrid placentas, which indicates that up-regulation in the hyperplastic placentas is a downstream event.
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| 28. |
- Singh, Umashankar, et al.
(författare)
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Expression and Functional Analysis of Fibulin-1 (Fbln1) During Normal and Abnormal Placental Development of the Mouse
- 2006
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Ingår i: Placenta. - : Elsevier BV. - 0143-4004 .- 1532-3102. ; 27:9-10, s. 1014-1021
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix protein fibulin-1 (FBLN1) is an important component of blood vessel walls, as shown by the lethality of mice with homozygous targeted deletion of the Fbln1 gene. Here, we show that a murine placental overgrowth phenotype is associated with elevated Fbln1 transcript levels, suggesting that the gene and its product have a functional role in placentation. Fbln1 exhibits a specific expression pattern in the mouse placenta. Transcripts could not be detected prior to day 12. In subsequent stages, Fbln1 was expressed strongly in the spongiotrophoblast. Other sites of expression were endothelia of large fetal blood vessels, a tissue type reported to not express this gene. In addition, a subset of giant cells expressed the gene. This giant cell specific expression was strongly increased in hyperplastic placentas. Analysis of the placentation in fibulin null mice did not show any abnormality. Attempts to rescue the placental phenotypes of a congenic model of interspecies hybrid placental dysplasia (IHPD) by normalizing expression of Fbln1 proved that Fbln1 alone is not the key cause of phenotypes in these models of placental hyperplasia.
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| 29. |
- Singh, Umashankar, 1977-
(författare)
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New Functions for Old Genes in the Mouse Placenta
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Different species are separated by pre-zygotic reproductive barriers which impede gene flow between them. Rarely, when pre-zygotic barriers break down, interspecific hybrids are produced that display abnormal phenotypes, collectively called hybrid dysgenesis effects. Interspecies hybrid placental dysplasia (IHPD) in the genus Mus is a very consistent X-linked hybrid dysgenesis effect. Reproductive cloning and mutation of the gene Esx1 lead to placental hyperplasias with phenotypic similarities to IHPD. Comparative gene expression analysis of these three different models of placental hyperplasia showed that different mechanisms underlie these placental hyperplasias. We also identified several genes for which roles in placentation had not been studied earlier. We screened five of these genes, Car2, Ncam1, Fbln1, Cacnb3 and Cpe for their functions in placentation. Analysis of the spatio-temporal expression patterns of these genes during mouse placental development showed that they are ectopically expressed in IHPD placentas. Placental phenotype and gene expression was then studied in mice mutant for these genes. Our results show that complicated by the expression of functional counterparts, deletion of these genes failed to produce any consistent phenotype. Incompletely penetrant phenotypes were found in Cacnb3 and Cpe mutants. The Cpe mutant placentas recapitulated some IHPD phenotypes, despite co-expression of Cpd, a functionally redundant gene. Deregulated expression of Cpe and Cpd prior to manifestation of IHPD phenotype indicated that these are causally involved in IHPD and might be speciation genes in the genus Mus. We found that AT24 placentas also exhibit deregulated expression of these genes and could be used as a model to study IHPD. We tried rescuing the AT24 placental phenotype, by decreasing the expression of the over expressed genes. Normalization of transcript levels of these genes did not rescue the AT24 phenotype, thus indicating that up-regulation of these genes is a down-stream event in the generation of IHPD.
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| 30. |
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| 31. |
- Svensson, Kristian, et al.
(författare)
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H19 is imprinted in the choroid plexus and leptomeninges of the mouse foetus
- 1995
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Ingår i: Mechanisms of Development. - 0925-4773 .- 1872-6356. ; 51:1, s. 31-37
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Tidskriftsartikel (refereegranskat)abstract
- It has been proposed that either the Igf-2 gene or the H19 gene — but not both — can be expressed from a given chromosome. Igf-2 is known to be biallelically expressed in the choroid plexus and leptomeninges, however, raising the question of whether H19 is down-regulated or absent there. We found by in situ hybridization that H19 is indeed expressed in the choroid plexus and leptomeninges of the developing mouse foetus. Comparison with the expression pattern of Igf-2 showed that the genes are coexpressed in all areas, with the exception of the choroid plexus epithelium. To evaluate whether H19 is also biallelically expressed in these tissues, we microdissected embryos from interspecific crosses and performed RNAse protection analysis on the isolated RNA. This revealed that H19 maintains its imprint in the choroid plexus/leptomeninges, being transcribed from the maternal allele at a level comparable to that in normal liver. We discuss the significance of these results for current models of Igf-2 and H19 imprinting.
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| 32. |
- Tian, Geng, et al.
(författare)
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Expression and function of the LIM homeobox containing genes Lhx3 and Lhx4 in the mouse placenta
- 2008
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Ingår i: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 237:5, s. 1517-1525
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Tidskriftsartikel (refereegranskat)abstract
- The LIM homeobox containing genes of the LIM-3 group, Lhx3 and Lhx4, are critical for normal development. Both genes are involved in the formation of the pituitary and the motoneuron system and loss of either gene causes perinatal lethality. Previous studies had shown that Lhx3 is overexpressed in hyperplastic placentas of mouse interspecies hybrids. To determine the role of LHX3 in the mouse placenta, we performed expression and function analyses. Our results show that Lhx3 exhibits specific spatial and temporal expression in the mouse placenta. However, deletion of Lhx3 does not produce a placental phenotype. To test whether this is due to functional substitution by Lhx4, we performed a phenotype analysis of Lhx3-/-; Lhx4-/- double-mutant placentas. A subset of Lhx3-/-; Lhx4-/- placentas exhibited abnormal structure of the labyrinth. However, absence of both LIM-3 genes did not interfere with placental transport nor consistently with expression of target genes such as Gnrhr. Thus, LHX3 and LHX4 appear to be dispensable for placental development and function.
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| 33. |
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| 34. |
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| 35. |
- Yu, Yang, 1970-
(författare)
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Molecular Mechanisms Underlying Abnormal Placentation in the Mouse
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Placental development can be disturbed by various factors, such as mutation of specific genes or maternal diabetes. Our previous work on interspecies hybrid placental dysplasia (IHPD) and two additional models of placental hyperplasia, cloned mice and Esx1 mutants, showed that many genes are deregulated in placental dysplasia. Two of these candidate placentation genes, Cpe and Lhx3, were further studied. We performed in situ hybridization to determine their spatio-temporal expression in the placentas and placental phenotypes were analyzed in mutant mice. Our results showed that the placental phenotype in Cpe mutant mice mimics some IHPD phenotypes. Deregulated expression of Cpe and Cpd, a functionally equivalent gene, prior to the manifestation of the IHPD phenotype, indicated that Cpe and Cpd are potentially causative genes in IHPD. Lhx3 mutants lacked any placental phenotype. Deletion of Lhx3 and Lhx4 together caused an inconsistent placental phenotype which did not affect placental lipid transport function or expression of Lhx3/Lhx4 target genes. Down regulation of Lhx3/Lhx4 did not rescue the placental phenotype of AT24 mice and hence could be excluded as causative genes in IHPD. Analysis of placental development in diabetic mice showed that severe maternal diabetes resulted in fetal intrauterine growth restriction (IUGR) without any change in placental weight and lipid transport function. The diabetic placentas however exhibited abnormal morphology. Gene expression profiling identified some genes that might contribute to diabetic pathology. In another study, it was found that the heterochromatin protein CBX1 is required for normal placentation, as deletion of the gene caused consistent spongiotrophoblast and labyrinthine phenotypes. Gene expression profiling and spatio-temporal expression analysis showed that several genes with known function in placental development were deregulated in the Cbx1 null placenta.
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| 36. |
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