Dataset Information

Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

ABSTRACT: 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.

SUBMITTER: Chau YY

PROVIDER: S-EPMC3245305 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

Chau You-Ying YY Brownstein David D Mjoseng Heidi H Lee Wen-Chin WC Buza-Vidas Natalija N Nerlov Claus C Jacobsen Sten Eirik SE Perry Paul P Berry Rachel R Thornburn Anna A Sexton David D Morton Nik N Hohenstein Peter P Freyer Elisabeth E Samuel Kay K van't Hof Rob R Hastie Nicholas N

PLoS genetics 20111222 12

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 on ...[more]

PMID: 22216009

Similar Datasets

Project description:The impact of extrapulmonary organ dysfunction, independent from sepsis and lung injury severity, on outcomes in pediatric acute respiratory failure is unclear. We sought to determine the frequency, timing, and risk factors for extrapulmonary organ dysfunction and the independent association of multiple organ dysfunction syndrome with outcomes in pediatric acute respiratory failure.Secondary observational analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure cluster-randomized prospective clinical trial conducted between 2009 and 2013.Thirty-one academic PICUs in the United States.Two thousand four hundred forty-nine children mechanically ventilated for acute respiratory failure enrolled in Randomized Evaluation of Sedation Titration for Respiratory Failure.Organ dysfunction was defined using criteria published for pediatric sepsis. Multiple organ dysfunction syndrome was defined as respiratory dysfunction one or more extrapulmonary organ dysfunctions. We used multivariable logistic regression to identify risk factors for multiple organ dysfunction syndrome, and logistic or proportional hazards regression to compare clinical outcomes. All analyses accounted for PICU as a cluster variable. Overall, 73% exhibited extrapulmonary organ dysfunction, including 1,547 (63%) with concurrent multiple organ dysfunction syndrome defined by onset on day 0/1 and 244 (10%) with new multiple organ dysfunction syndrome with onset on day 2 or later. Most patients (93%) with indirect lung injury from sepsis presented with concurrent multiple organ dysfunction syndrome, whereas patients with direct lung injury had both concurrent (56%) and new (12%) multiple organ dysfunction syndrome. Risk factors for concurrent multiple organ dysfunction syndrome included older age, illness severity, sepsis, cancer, and moderate/severe lung injury. Risk factors for new multiple organ dysfunction syndrome were moderate/severe lung injury and neuromuscular blockade. Both concurrent and new multiple organ dysfunction syndrome were associated with 90-day in-hospital mortality (concurrent: adjusted odds ratio, 6.54; 95% CI, 3.00-14.25 and new: adjusted odds ratio, 3.21; 95% CI, 1.48-6.93) after adjusting for sepsis, moderate/severe lung injury, and other baseline characteristics.Extrapulmonary organ dysfunction was common, generally occurred concurrent with respiratory dysfunction (especially in sepsis), and was a major risk factor for mortality in pediatric acute respiratory failure.

Dataset Information

Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

Publications

Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets