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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| Language: | English |
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Public Library of Science (PLoS)
2011-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002404&type=printable |
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| author | You-Ying Chau David Brownstein Heidi Mjoseng Wen-Chin Lee Natalija Buza-Vidas Claus Nerlov Sten Eirik Jacobsen Paul Perry Rachel Berry Anna Thornburn David Sexton Nik Morton Peter Hohenstein Elisabeth Freyer Kay Samuel Rob van't Hof Nicholas Hastie |
| author_facet | You-Ying Chau David Brownstein Heidi Mjoseng Wen-Chin Lee Natalija Buza-Vidas Claus Nerlov Sten Eirik Jacobsen Paul Perry Rachel Berry Anna Thornburn David Sexton Nik Morton Peter Hohenstein Elisabeth Freyer Kay Samuel Rob van't Hof Nicholas Hastie |
| author_sort | You-Ying Chau |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-5b754ee38bb04229ad7234cf55d68a2e |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-5b754ee38bb04229ad7234cf55d68a2e2025-08-20T03:26:39ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-12-01712e100240410.1371/journal.pgen.1002404Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.You-Ying ChauDavid BrownsteinHeidi MjosengWen-Chin LeeNatalija Buza-VidasClaus NerlovSten Eirik JacobsenPaul PerryRachel BerryAnna ThornburnDavid SextonNik MortonPeter HohensteinElisabeth FreyerKay SamuelRob van't HofNicholas HastieThere 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002404&type=printable |
| spellingShingle | You-Ying Chau David Brownstein Heidi Mjoseng Wen-Chin Lee Natalija Buza-Vidas Claus Nerlov Sten Eirik Jacobsen Paul Perry Rachel Berry Anna Thornburn David Sexton Nik Morton Peter Hohenstein Elisabeth Freyer Kay Samuel Rob van't Hof Nicholas Hastie Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1. PLoS Genetics |
| 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 |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002404&type=printable |
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