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Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1

There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is...

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Autores principales: Chau, You-Ying, Brownstein, David, Mjoseng, Heidi, Lee, Wen-Chin, Buza-Vidas, Natalija, Nerlov, Claus, Jacobsen, Sten Eirik, Perry, Paul, Berry, Rachel, Thornburn, Anna, Sexton, David, Morton, Nik, Hohenstein, Peter, Freyer, Elisabeth, Samuel, Kay, van't Hof, Rob, Hastie, Nicholas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245305/
https://www.ncbi.nlm.nih.gov/pubmed/22216009
http://dx.doi.org/10.1371/journal.pgen.1002404
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author Chau, You-Ying
Brownstein, David
Mjoseng, Heidi
Lee, Wen-Chin
Buza-Vidas, Natalija
Nerlov, Claus
Jacobsen, Sten Eirik
Perry, Paul
Berry, Rachel
Thornburn, Anna
Sexton, David
Morton, Nik
Hohenstein, Peter
Freyer, Elisabeth
Samuel, Kay
van't Hof, Rob
Hastie, Nicholas
author_facet Chau, You-Ying
Brownstein, David
Mjoseng, Heidi
Lee, Wen-Chin
Buza-Vidas, Natalija
Nerlov, Claus
Jacobsen, Sten Eirik
Perry, Paul
Berry, Rachel
Thornburn, Anna
Sexton, David
Morton, Nik
Hohenstein, Peter
Freyer, Elisabeth
Samuel, Kay
van't Hof, Rob
Hastie, Nicholas
author_sort Chau, You-Ying
collection PubMed
description There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal–epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover.
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spelling pubmed-32453052012-01-03 Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1 Chau, You-Ying Brownstein, David Mjoseng, Heidi Lee, Wen-Chin Buza-Vidas, Natalija Nerlov, Claus Jacobsen, Sten Eirik Perry, Paul Berry, Rachel Thornburn, Anna Sexton, David Morton, Nik Hohenstein, Peter Freyer, Elisabeth Samuel, Kay van't Hof, Rob Hastie, Nicholas PLoS Genet Research Article There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal–epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover. Public Library of Science 2011-12-22 /pmc/articles/PMC3245305/ /pubmed/22216009 http://dx.doi.org/10.1371/journal.pgen.1002404 Text en Chau et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chau, You-Ying
Brownstein, David
Mjoseng, Heidi
Lee, Wen-Chin
Buza-Vidas, Natalija
Nerlov, Claus
Jacobsen, Sten Eirik
Perry, Paul
Berry, Rachel
Thornburn, Anna
Sexton, David
Morton, Nik
Hohenstein, Peter
Freyer, Elisabeth
Samuel, Kay
van't Hof, Rob
Hastie, Nicholas
Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1
title Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1
title_full Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1
title_fullStr Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1
title_full_unstemmed Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1
title_short Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1
title_sort acute multiple organ failure in adult mice deleted for the developmental regulator wt1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245305/
https://www.ncbi.nlm.nih.gov/pubmed/22216009
http://dx.doi.org/10.1371/journal.pgen.1002404
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