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.
Vyšlo v časopise:
Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002404
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002404
Souhrn
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.
Zdroje
1. LepperCConwaySJFanCM 2009 Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements.
Nature 460
627 631
2. KimISaundersTLMorrisonSJ 2007 Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell
130 470
483
3. HohensteinPHastieND 2006 The many facets of the Wilms' tumour gene, WT1.
Hum Mol Genet 15 Spec No 2
R196 201
4. KreidbergJASariolaHLoringJMMaedaMPelletierJ 1993 WT-1 is required for early kidney development. Cell
74 679
691
5. Martinez-EstradaOMLetticeLAEssafiAGuadixJASlightJ 2010 Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nat Genet
42 89 93
6. WilmBIpenbergAHastieNDBurchJBBaderDM 2005 The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature.
Development 132
5317 5328
7. QueJWilmBHasegawaHWangFBaderD 2008 Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development.
Proc Natl Acad Sci U S A 105
16626 16630
8. IjpenbergAPerez-PomaresJMGuadixJACarmonaRPortillo-SanchezV 2007 Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis. Dev Biol
312 157
170
9. GuadixJARuiz-VillalbaALetticeLVelecelaVMunoz-ChapuliR 2011 Wt1 controls retinoic acid signalling in embryonic epicardium through transcriptional activation of Raldh2. Development
138 1093
1097
10. AsahinaKZhouBPuWTTsukamotoH 2011 Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology
53 983
995
11. FriedmanSL 2008 Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.
Physiol Rev 88
125 172
12. MasamuneAShimosegawaT 2009 Signal transduction in pancreatic stellate cells. J Gastroenterol 44 249
260
13. VonlaufenAJoshiSQuCPhillipsPAXuZ 2008 Pancreatic stellate cells: partners in crime with pancreatic cancer cells.
Cancer Res 68
2085 2093
14. WalkerCRuttenFYuanXPassHMewDM 1994 Wilms' tumor suppressor gene expression in rat and human mesothelioma.
Cancer Res 54
3101 3106
15. ArmstrongJFPritchard-JonesKBickmoreWAHastieNDBardJB 1993 The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo. Mech Dev 40
85 97
16. RaoMKPhamJImamJSMacLeanJAMuraliD 2006 Tissue-specific RNAi reveals that WT1 expression in nurse cells controls germ cell survival and spermatogenesis. Genes Dev
20 147
152
17. PelletierJSchallingMBucklerAJRogersAHaberDA 1991 Expression of the Wilms' tumor gene WT1 in the murine urogenital system.
Genes Dev 5
1345 1356
18. HosenNShirakataTNishidaSYanagiharaMTsuboiA 2007 The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis.
Leukemia 21
1783 1791
19. HammesAGuoJKLutschGLehesteJRLandrockD 2001 Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Cell
106 319
329
20. RosenfeldCCheeverMAGaigerA 2003 WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies.
Leukemia 17 1301
1312
21. King-UnderwoodLLittleSBakerMClutterbuckRDelassusS 2005 Wt1 is not essential for hematopoiesis in the mouse.
Leuk Res 29 803
812
22. NakatsukaSOjiYHoriuchiTKandaTKitagawaM 2006 Immunohistochemical detection of WT1 protein in a variety of cancer cells.
Mod Pathol 19
804 814
23. MolletGRateladeJBoyerOMudaAOMorissetL 2009 Podocin inactivation in mature kidneys causes focal segmental glomerulosclerosis and nephrotic syndrome. J Am Soc Nephrol
20 2181
2189
24. GoldbergSAdair-KirkTLSeniorRMMinerJH 2010 Maintenance of Glomerular Filtration Barrier Integrity Requires Laminin {alpha}5.
J Am Soc Nephrol
25. DaiCStolzDBBastackySISt-ArnaudRWuC 2006 Essential role of integrin-linked kinase in podocyte biology: Bridging the integrin and slit diaphragm signaling. J Am Soc Nephrol 17 2164
2175
26. PhilippeAWeberSEsquivelELHoubronCHamardG 2008 A missense mutation in podocin leads to early and severe renal disease in mice.
Kidney Int 73
1038 1047
27. SierigRKruspeDKastnerJLckCWitzgallR The Wilms tumour protein is required for kidney function in adult mice 2009;
Edinburgh, Scotland, UK S152
28. ShimamuraRFraizerGCTrapmanJLau YfCSaundersGF 1997 The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Mullerian-inhibiting substance, and the androgen receptor. Clin Cancer Res
3 2571 2580
29. HerzerUCrocollABartonDHowellsNEnglertC 1999 The Wilms tumor suppressor gene wt1 is required for development of the spleen. Curr Biol 9
837 840
30. KouryMJ 2005 Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone.
Exp Hematol 33
1263 1270
31. DameCKirschnerKMBartzKVWallachTHusselsCS 2006 Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. Blood 107
4282 4290
32. WagersAJ 2005 Stem cell grand SLAM. Cell
121 967 970
33. PronkCJRossiDJManssonRAttemaJLNorddahlGL 2007 Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell
1 428 442
34. FuentesRWangYHirschJWangCRauovaL Infusion of mature megakaryocytes into mice yields functional platelets. J Clin Invest 120 3917
3922
35. ApteMVHaberPSApplegateTLNortonIDMcCaughanGW 1998 Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture.
Gut 43
128 133
36. AhimaRSPrabakaranDMantzorosCQuDLowellB 1996 Role of leptin in the neuroendocrine response to fasting.
Nature 382
250 252
37. FaggioniRMoserAFeingoldKRGrunfeldC 2000 Reduced leptin levels in starvation increase susceptibility to endotoxic shock.
Am J Pathol 156
1781 1787
38. GaetkeLMOzHSFrederichRCMcClainCJ 2003 Anti-TNF-alpha antibody normalizes serum leptin in IL-2 deficient mice.
J Am Coll Nutr 22
415 420
39. KerstenSMandardSTanNSEscherPMetzgerD 2000 Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem
275 28488
28493
40. ShinmuraKTamakiKSaitoKNakanoYTobeT 2007 Cardioprotective effects of short-term caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase. Circulation
116 2809
2817
41. MaegawaSHinkalGKimHSShenLZhangL Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20 332
340
42. CalviLMAdamsGBWeibrechtKWWeberJMOlsonDP 2003 Osteoblastic cells regulate the haematopoietic stem cell niche.
Nature 425 841
846
43. SacchettiBFunariAMichienziSDi CesareSPiersantiS 2007 Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.
Cell 131
324 336
44. SjogrenKLiuJLBladKSkrticSVidalO 1999 Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice.
Proc Natl Acad Sci U S A 96
7088 7092
45. YakarSRosenCJBeamerWGAckert-BicknellCLWuY 2002 Circulating levels of IGF-1 directly regulate bone growth and density.
J Clin Invest 110
771 781
46. JessenBAStevensGJ 2002 Expression profiling during adipocyte differentiation of 3T3-L1 fibroblasts.
Gene 299
95 100
47. KratchmarovaIKalumeDEBlagoevBSchererPEPodtelejnikovAV 2002 A proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes. Mol Cell Proteomics 1 213
222
48. InagakiTDutchakPZhaoGDingXGautronL 2007 Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab
5 415 425
49. MiyagawaKKentJMooreACharlieuJPLittleMH 1998 Loss of WT1 function leads to ectopic myogenesis in Wilms' tumour.
Nat Genet 18
15 17
50. SchumacherVSchneiderSFiggeAWildhardtGHarmsD 1997 Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc Natl Acad Sci U S A 94 3972
3977
51. SchumacherVSchuhenSSonnerSWeirichALeuschnerI 2003 Two molecular subgroups of Wilms' tumors with or without WT1 mutations.
Clin Cancer Res 9
2005 2014
52. OmaryMBLugeaALoweAWPandolSJ 2007 The pancreatic stellate cell: a star on the rise in pancreatic diseases.
J Clin Invest 117
50 59
53. WagnerNWagnerKDXingYScholzHSchedlA 2004 The major podocyte protein nephrin is transcriptionally activated by the Wilms' tumor suppressor WT1. J Am Soc Nephrol
15 3044
3051
54. MiyataEMasuyaMYoshidaSNakamuraSKatoK 2008 Hematopoietic origin of hepatic stellate cells in the adult liver.
Blood 111
2427 2435
55. OkaYTsuboiAElisseevaOANakajimaHFujikiF 2007 WT1 peptide cancer vaccine for patients with hematopoietic malignancies and solid cancers. ScientificWorldJournal
7 649 665
56. CohenDESupinskiAMBonkowskiMSDonmezGGuarenteLP 2009 Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction.
Genes Dev 23
2812 2817
57. HeinrichsCColliMYanovskiJALaueLGerstlNA 1997 Effects of fasting on the growth plate: systemic and local mechanisms.
Endocrinology 138
5359 5365
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 12
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