Restricted Distribution of Tetraploid Cells in Mouse Tetraploid ↔ Diploid Chimaeras

James, Roberta M.; Klerkx, Anke H.E.M.; Keighren, Margaret; Flockhart, Jean H.; West, John D.

doi:10.1006/dbio.1995.1018

Cited by 96 publications

(78 citation statements)

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“…Studies at E12.5 and E7.5 have revealed that 4n cells are not simply restricted to extraembryonic tissues but more specifically to trophectoderm and primitive endoderm derivatives (James et al 1995). We also demonstrated that, as a group, 4n 2n blastocysts show a statistically significant greater contribution of 4n cells to the mural trophectoderm than to the inner cell mass or polar trophectoderm .…”

Section: supporting

confidence: 52%

Three‐dimensional reconstruction of tetraploid↔diploid chimaeric mouse blastocysts

et al. 2000

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Studies of tetraploid diploid (4n 2n) mouse chimaeras have demonstrated unequal contributions of 4n cells to different tissues of the midgestation conceptus. Such a pattern has also been reported in chimaeras as early as E3.5d, which show an enhanced contribution of 4n cells to the mural trophectoderm . In this study, sectioned 4n 2n and 2n 2n control chimaeric blastocysts were digitised and reconstructed in 3 dimensions (3-D). The 3-D images revealed only limited mixing of cells from the 2 contributing embryos of individual blastocysts in both chimaera groups. Consequently, the distribution pattern of the 2 cell types was dependent on the spatial relationship between the orientation of the blastocyst and the boundary between the 2 clusters of cells. The distribution patterns observed were not strikingly different for 4n 2n and 2n 2n chimaeras, each showing some transgenic positive cell contribution in all 3 identifiable developmental lineages. It was notable, however, that in all 4n 2n blastocysts at least some 4n cells were located adjacent to the blastocyst cavity. Such a consistent pattern was not evident in 2n 2n chimaeras. This study has demonstrated the value of 3-D reconstructions for the analysis of spatial relationships of 2 cell populations in chimaeric mouse blastocysts.Key words : Tetraploidy ; blastocyst ; chimaera ; chimera ; embryo. Tetraploid cells (4n) have been shown to be distributed nonrandomly in mouse postimplantation tetraploid\ diploid (4n\2n) mosaics (Tarkowski et al. 1977) and 4n 2n chimaeras (Lu & Markert, 1980 ;Nagy et al. 1990 ;James et al. 1995), readily contributing to the extraembryonic tissues but rarely to the fetus itself. Studies at E12.5 and E7.5 have revealed that 4n cells are not simply restricted to extraembryonic tissues but more specifically to trophectoderm and primitive endoderm derivatives (James et al. 1995). We also demonstrated that, as a group, 4n 2n blastocysts show a statistically significant greater contribution of 4n cells to the mural trophectoderm than to the inner cell mass or polar trophectoderm . This phenomenon appears to be related to ploidy not cell size at aggregation and Three-dimensional (3-D) reconstruction is potentially an extremely powerful tool for visualising the distribution of cell types within embryos. We produced 4n 2n aggregation chimaeras, in which the tetraploid component was hemizygous for the β-globin transgene TgN(Hbb-1)83Clo (Lo et al. 1987), and analysed them at the blastocyst stage by computer-aided 3-D reconstruction of histological sections. The aims were (1) to evaluate the use of 3-D reconstruction for the analysis of cell distributions in chimaeras and (2) to test whether any consistent pattern could be distinguished for the distribution of 4n cells in individual E3.5 4n 2n chimaeric blastocysts. Preliminary results from this study have been published in abstract form .

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Section: supporting

confidence: 52%

Three‐dimensional reconstruction of tetraploid↔diploid chimaeric mouse blastocysts

et al. 2000

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“…1A). Under these circumstances, wild-type tetraploid cells contribute exclusively to the placenta, whereas diploid cells contribute primarily to the embryo proper, with some contribution to the labyrinth of the placenta (19). As reported previously, this strategy led us to recover several live and apparently normal Rb Ϫ/Ϫ embryos, at developmental stages where no Rb Ϫ/Ϫ embryos derived from natural matings can be recovered (15).…”

Section: Resultsmentioning

confidence: 75%

Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb -deficient mice

Bruin

Saavedra

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

119

102

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Retinoblastoma (Rb)-deficient embryos show severe defects in neurogenesis, erythropoiesis, and lens development and die at embryonic day 14.5. Our recent results demonstrated a drastic disorganization of the labyrinth layer in the placenta of Rbdeficient embryos, accompanied by reduced placental transport function. When these Rb ؊/؊ embryos were supplied with a wildtype placenta by using either tetraploid aggregation or genetic approaches, animals survived until birth. Here we analyze the role of extraembryonic Rb in regulating proliferation, apoptosis, and differentiation in the rescued animals at different developmental stages. Many of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb ؊/؊ animals, including the ectopic apoptosis in the CNS, were virtually absent in rescued Rb ؊/؊ pups. However, rescued animals died at birth with severe skeletal muscle defects. Like in Rb knockout embryos, rescued animals showed a marked increase in DNA replication and cell division in the CNS. In sharp contrast, the typical widespread neuronal apoptosis was absent in Rb-deficient embryos reconstituted with a normal placenta. In lens fiber cells, however, the inappropriate proliferation and apoptosis that is normally observed in Rb ؊/؊ embryos continued unabated in rescued animals. These results demonstrate that Rb function in extraembryonic lineages plays an important role in the survival of neuronal cells and in the differentiation of the erythroid lineage, providing mechanistic insight into the cell autonomous and nonautonomous functions of Rb during development.

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“…Tetraploid cells are severely limited in their ability to contribute to embryonic tissues (31,32) and therefore contribute primarily to the placenta, whereas diploid cells in aggregates contribute primarily to the embryo proper (31,33). Here, tetraploid embryos were derived from matings between wild-type mice, and these were aggregated with diploid embryos derived from matings between Fatp4 ϩ/Ϫ mice, of which 1 ⁄ 4 are expected to be Fatp4 Ϫ/Ϫ embryos.…”

Section: Restoration Of Fatp4mentioning

confidence: 99%

Keratinocyte-specific Expression of Fatty Acid Transport Protein 4 Rescues the Wrinkle-free Phenotype in Slc27a4/Fatp4 Mutant Mice

Moulson

Lin

White

et al. 2007

Journal of Biological Chemistry

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FATP4 (fatty acid transport protein 4; also known as SLC27A4) is the most widely expressed member of a family of six long chain fatty acid transporters. FATP4 is highly expressed in enterocytes and has therefore been proposed to be a major importer of dietary fatty acids. Two independent mutations in Fatp4 cause mice to be born with thick, tight, shiny, "wrinklefree" skin and a defective skin barrier; they die within hours of birth from dehydration and restricted movements. In contrast, induced keratinocyte-specific deficiency of FATP4 in adult mice causes only mild skin abnormalities. Therefore, whether the loss of FATP4 from skin or a systemic gestational metabolic defect causes the severe skin defects and neonatal lethality remain important unanswered questions. To investigate the basis for the phenotype, we first generated wild-type tetraploid/mutant diploid aggregates that should lead to rescue of any abnormalities caused by loss of FATP4 from the placenta. However, the skin phenotype was not ameliorated. We then generated transgenic mice expressing exogenous FATP4 either widely or specifically in suprabasal keratinocytes, and we bred the transgenes onto the Fatp4 ؊/؊ background. Both modes of FATP4 expression led to rescue of the neonatally lethal skin defects, and the resulting mice were viable and fertile. Keratinocyte expression of an FATP4 variant with mutations in the acyl-CoA synthetase domain did not provide any degree of rescue. We conclude that expression of FATP4 with an intact acyl-CoA synthetase domain in suprabasal keratinocytes is necessary for normal skin development and that FATP4 functions in establishing the cornified envelope. Fatty acid transport proteins (FATPs)2 compose a family of transmembrane proteins that facilitate cellular long chain fatty acid uptake (1-3). The most widely expressed member of this family is FATP4 (4, 5), which is encoded by Slc27a4 (solute carrier family 27 member 4 gene). The most robust expression of FATP4 is in intestinal epithelial cells (5), but its broad expression pattern is suggestive of functions in many organs.Surprisingly, the "wrinkle-free" phenotype we discovered in mice with a spontaneous mutation in Slc27a4 (Slc27a4 wrfr ) and the identical phenotype of mice with a targeted Slc27a4 mutation (Slc27a4) indicate critical roles for FATP4 in skin and hair development (6, 7). For these mutations, which both affect exon 3, homozygotes are born with tight, thick, shiny skin and a defective skin barrier; they die shortly after birth because of restricted movements and dehydration. These defects are reminiscent of human restrictive dermopathy, but this disease has recently been linked to mutations in zinc metalloproteinase STE24 (8 -10). Interestingly, deletion of Slc27a4 exons 2 and 3 (the first two coding exons; Slc27a4 tm1Asta ) results in embryonic lethality prior to embryonic day 9.5 (11). The reason for the striking difference in phenotypes remains unknown, but it may involve a partially functional truncated protein in the first two mutants or early ...

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Restricted Distribution of Tetraploid Cells in Mouse Tetraploid ↔ Diploid Chimaeras

Cited by 96 publications

References 0 publications

Three‐dimensional reconstruction of tetraploid↔diploid chimaeric mouse blastocysts

Three‐dimensional reconstruction of tetraploid↔diploid chimaeric mouse blastocysts

Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb -deficient mice

Keratinocyte-specific Expression of Fatty Acid Transport Protein 4 Rescues the Wrinkle-free Phenotype in Slc27a4/Fatp4 Mutant Mice

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