1. WT1 – A Complex Life
By: Chen Zhu

2. WT1 – Outline Introduction Function Structure Role in development
In mice
In humans
Role in cancer
Wilm’s Tumor, related illnesses

3. Introduction Wilms’ Tumor 1 (WT1) is found on human chromosome 11p13
WT1 is important for the development of the genitourinary system and mesothelial tissues.
The inactivation of WT1 is responsible for ~10-15% of Wilms’ tumor

4. Function WT1 is a transcriptional and post-transcriptional regulator
It contains signals that allow it to localize inside the nucleus
It contains domains that can bind to several DNA sequences

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6. Structure
WT1 is a 50kb gene with ten exons, together encoding a mRNA of ~3kb.
The N-terminus of WT1 contains a proline and glutamine-rich region that facilitates homodimerization
There are two alternatively spliced exons in WT1

7. Exon 5
Exon 5 encodes 17 amino acids between the N-terminus and the first Zn finger domain
Encodes a protein-protein interaction domain

8. Exon 9
Encodes the sequence KTS between the third and fourth zinc fingers of the protein
WT1 (-KTS) variants have been shown to act as transcriptional regulators1
WT1 (+KTS) may play a role in RNA processing.

9. Adapted from Figure 5 in Keith W. Brown and Karim T. A
Adapted from Figure 5 in Keith W. Brown and Karim T.A. Malik, “The molecular biology of Wilms’ Tumor,” Exp. Rev. Mol. Med. 14 May,

10. Alternate Splicing 24 alternate isoforms of WT1 have been described
(+KTS)/(-KTS) is by far the most important alternate splicing mechanism

11. Function Many target genes of WT1 have been identified
The role of WT1 in transcriptional regulation, however, is not well understood

12. Function
We do understand, however, that WH1 is involved in many different pathways:
The differentiation of leukemic cell lines
The differentiation of pheochromocytoma cells
Both the induction and prevention of apoptosis

13. WT1 Target Genes2

14. Role In Development
WT1 is expressed during development in the following systems:
Urinogenital system
Epicardium and subepicardial mesenchyme
(heart)
Kidneys
Spleen
Parts of the brain
Spinal chord
Mesothelial organs
Diaphram

15. Jordan A. Kreidberg, et al
Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: (1993)

16. Knockout Mice
WT1 (-/-) die from embryonic day 12 to the end of gestation
Many defects are evident in many of the areas mentioned in the previous slide
Mutant embryos lack kidneys and gonads

17. Heterozygous Mice
WT1 (+/-) mice usually die after several months due to renal insufficiency
The severity of symptoms can be correlated with WT1 levels
Symptoms are similar to the human Frasier Syndrome

18. Jordan A. Kreidberg, et al
Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: (1993)

19. Kidney Development
Loose mesenchyme forms epithelial condenses around ureteric bud tips
S-shaped bodies develop and eventually elongate to attach to the collecting duct

20. Kidney Development -The role of WT1
Without WT1, the loose mesenchyme becomes apoptotic
WT1 may thus act as a survival factor for populations of embryonic kidney cells during development
An antiapoptotic protein encoded by Bcl-2 may be an upstream mediator of WT1

21. Heart Development
WT1(-/-) mutants show smaller hearts and thinning of muscular walls
The epicarium, especially, requires WT1
WT1 is thought to play a role in the transformation of epicardial to mesenchymal cells

22. Jordan A. Kreidberg, et al
Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: (1993)

23. Role In Cancer WAGR: heterozygous deletions at chromosome 11p13
Frasier Syndrome : heterozygous point mutations in intron 9
Leukemia: heterozygous WT1 mutations

24. WAGR WAGR is a syndrome for affected children predisposed to develop:
Wilms’ tumor
Aniridia
Genitourinary anomalies
mental Retardation

25. WAGR Aniridia Genitourinary Anomalies Mental Retardation

26. Wilm’s Tumor Wilms’ Tumor is a cancer of the kidney
About 500 cases are diagnosed yearly
Onset is early, with nearly everybody diagnosed under the age of 25
Survival with therapy is very good: ~85%
WAGR patients should undergo frequent ultrasound testing

27. Wilm’s Tumor
Wilm’s tumor arises from mesenchyme that fails to differentiate into the epithelial component of the nephron
Inactivation of WT1 produces foci of primitive renal cells called nephrogenic rests
Sometimes called tri-phasic type, consisting of undifferentiated mesenchyme, stromal and epiphelial cells

28. Leukemia
WT1 is inappropriately expressed in many Leukemia cell lines (~15%)
WT1 is usually expressed in stem cells of bone marrow, but not in normal mature blood cells, linking it to an immature state for leukemia cells
WT1 expression levels increase during the progression of acute myeloid leukemia
Patients with low WT1 mRNA had a better prognosis than those with high WT1 mRNA

29. Questions?

30. Bibliography
Holger Scholz and Karin M. Kirschner, “A Role for the Wilms’ Tumor Protein WT1 in Organ Development,” Physiology 20: (2005)
Volkher Scharnhorst, et al., “WT1 proteins: functions in growth and differentiation,” Gene 273: (2001)
Kay-Dietrich Wagner, et al., “The complex life of WT1,” Journal of Cell Science 116: (2003)
Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: (1993)
National Cancer institute, “Wilms’ Tumor and Other Childhood Kidney Tumors,” November 27, <
International WAGR Syndrome Association, “What is WAGR Syndrome?” Accessed April 27, <
Monika L. Metzger, Jeffrey S. Dome., “Current Therapy for Wilms’ Tumor,” Oncologist 10: (2005)