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.

Author Summary

It is important to understand the cellular and molecular pathways that regulate the maintenance and turnover of adult tissues. These processes often go awry in diseases and are likely to deteriorate with ageing. Here we show that removal of a single gene, the Wilms' Tumour gene, Wt1, in the adult mouse leads to the extremely rapid deterioration of multiple tissues. Within 7–9 days after gene removal kidneys fail, the pancreas and spleen suffer severe atrophy, there is widespread loss of bone and body fat, and red blood cells are no longer produced. Our findings reveal the vulnerability of adult tissues, while opening up avenues for dissecting the pathways controlling tissue turnover. Further experiments showed that the tissue failure we observed is due both to local defects of stem/progenitor cell activities and to significant changes in the serum levels of some key master regulators. In particular there is a dramatic reduction in the levels of IGF-1, a key regulator of homeostasis and aging. Our studies also show that the control of adult tissue turnover may be different from that during foetal development. These findings have important implications for understanding and treating common human diseases.