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 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.
Medical Research Council Human Genetics Unit and the Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom.
You-Ying
YY
Chau
David
D
Brownstein
Heidi
H
Mjoseng
Wen-Chin
WC
Lee
Natalija
N
Buza-Vidas
Claus
C
Nerlov
Sten Eirik
SE
Jacobsen
Paul
P
Perry
Rachel
R
Berry
Anna
A
Thornburn
David
D
Sexton
Nik
N
Morton
Peter
P
Hohenstein
Elisabeth
E
Freyer
Kay
K
Samuel
Rob
R
van't Hof
Nicholas
N
Hastie
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology; D006066:Gonads / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009102:Multiple Organ Failure / Q000235:genetics* / Q000473:pathology; D046790:Pancreas, Exocrine / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D025721:WT1 Proteins / Q000235:genetics / Q000502:physiology*
D008565:Membrane Proteins; D025721:WT1 Proteins; C519530:insulin-like growth factor-1, mouse; C113267:nephrin; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I