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Carboxypeptidase E in the mouse placenta
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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2006 (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 74, no 9-10, 648-660 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2006. Vol. 74, no 9-10, 648-660 p.
Keyword [en]
interspecies hybrid placental dysplasia, Cpe, Cpd, fat mutation, trophoblast giant cells
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94491DOI: 10.1111/j.1432-0436.2006.00093.xISI: 000242657200016PubMedID: 17177860OAI: oai:DiVA.org:uu-94491DiVA: diva2:168357
Available from: 2006-05-08 Created: 2006-05-08 Last updated: 2017-12-14Bibliographically 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)
Opponent
Supervisors
Available from: 2006-05-08 Created: 2006-05-08 Last updated: 2009-04-05Bibliographically approved
2. Molecular Mechanisms Underlying Abnormal Placentation in the Mouse
Open this publication in new window or tab >>Molecular Mechanisms Underlying Abnormal Placentation in the Mouse
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 371
Keyword
Developmental biology, IUGR, Placental phenotype, Placental hyperplasia, Diabetes, IHPD, Utvecklingsbiologi
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-8331 (URN)978-91-554-7037-1 (ISBN)
Public defence
2007-12-12, Lindahlsalen, EBC, 18A, Norbyvägen, Uppsala, 75236., 10:00 (English)
Opponent
Supervisors
Available from: 2007-11-21 Created: 2007-11-21 Last updated: 2010-02-04Bibliographically approved

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Fundele, Reinald H.

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