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Expression and Functional Analysis of Genes Deregulated in Mouse Placental Overgrowth Models: Car2 and Ncam1
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
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2005 (English)In: Developmental Dynamics, ISSN 1058-8388, Vol. 234, no 4, 1034-1045 p.Article in journal (Refereed) Published
Abstract [en]

Different causes, such as maternal diabetes, cloning by nuclear transfer, interspecific hybridization, and deletion of some genes such as Esx1, Ipl, or Cdkn1c, may underlie placental overgrowth. In a previous study, we carried out comparative gene expression analysis in three models of placental hyperplasias, cloning, interspecies hybridization (IHPD), and Esx1 deletion. This study identified a large number of genes that exhibited differential expression between normal and enlarged placentas; however, it remained unclear how altered expression of any specific gene was related to any specific placental phenotype. In the present study, we focused on two genes, Car2 and Ncam1, which both exhibited increased expression in interspecies and cloned hyperplastic placentas. Apart from a detailed expression analysis of both genes during normal murine placentation, we also assessed morphology of placentas that were null for Car2 or Ncam1. Finally, we attempted to rescue placental hyperplasia in a congenic model of IHPD by decreasing transcript levels of Car2 or Ncam1. In situ analysis showed that both genes are expressed mainly in the spongiotrophoblast, however, expression patterns exhibited significant variability during development. Contrary to expectations, homozygous deletion of either Car2 or Ncam1 did not result in placental phenotypes. However, expression analysis of Car3 and Ncam2, which can take over the function of Car2 and Ncam1, respectively, indicated a possible rescue mechanism, as Car3 and Ncam2 were expressed in spongiotrophoblast of Car2 and Ncam1 mutant placentas. On the other hand, downregulation of either Car2 or Ncam1 did not rescue any of the placental phenotypes of AT24 placentas, a congenic model for interspecies hybrid placentas. This strongly suggested that altered expression of Car2 and Ncam1 is a downstream event in placental hyperplasia.

Place, publisher, year, edition, pages
2005. Vol. 234, no 4, 1034-1045 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94488DOI: 10.1002/dvdy.20597PubMedID: 16247769OAI: oai:DiVA.org:uu-94488DiVA: diva2:168354
Available from: 2006-05-08 Created: 2006-05-08 Last updated: 2010-02-05Bibliographically approved
In thesis
1. New Functions for Old Genes in the Mouse Placenta
Open this publication in new window or tab >>New Functions for Old Genes in the Mouse Placenta
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 181
Keyword
Developmental biology, hybrid dysgenesis effects, placental hyperplasia, functional screening, giant cell, glycogen cell, Utvecklingsbiologi
Identifiers
urn:nbn:se:uu:diva-6882 (URN)91-554-6566-8 (ISBN)
Public defence
2006-05-30, Lindahlsalen, EBC, Norbyvägen 18A, Uppsala, 10:00 (English)
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Available from: 2006-05-08 Created: 2006-05-08 Last updated: 2009-04-05Bibliographically approved

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