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WT1 – A Complex Life
By: Chen Zhu
WT1 – Outline
Introduction
 Function
 Structure
 Role in development
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In mice
In humans
Role in cancer
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Wilm’s Tumor, related illnesses
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

Function
WT1 is a transcriptional and posttranscriptional 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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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

Exon 5
Exon 5 encodes 17 amino acids between
the N-terminus and the first Zn finger
domain
 Encodes a protein-protein interaction
domain

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.

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, http://www.expertreviews.org/01003027h.htm
Alternate Splicing
24 alternate isoforms of WT1 have been
described
 (+KTS)/(-KTS) is by far the most
important alternate splicing mechanism

Function
Many target genes of WT1 have been
identified
 The role of WT1 in transcriptional
regulation, however, is not well
understood

Function

We do understand, however, that WH1 is
involved in many different pathways:
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The differentiation of leukemic cell lines
The differentiation of pheochromocytoma cells
Both the induction and prevention of apoptosis
WT1 Target Genes2
Role In Development

WT1 is expressed during development in the
following systems:
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Urinogenital system
Epicardium and subepicardial mesenchyme
(heart)
Kidneys
Spleen
Parts of the brain
Spinal chord
Mesothelial organs
Diaphram
Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
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

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

Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
Kidney Development
Loose mesenchyme forms epithelial
condenses around ureteric bud tips
 S-shaped bodies develop and eventually
elongate to attach to the collecting duct

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
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Heart Development
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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
Jordan A. Kreidberg, et al., “WT-1 is required for early liver development,” Cell 74: 679-691 (1993)
Role In Cancer
WAGR: heterozygous deletions at
chromosome 11p13
 Frasier Syndrome : heterozygous point
mutations in intron 9
 Leukemia: heterozygous WT1 mutations
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WAGR
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WAGR is a syndrome for affected children
predisposed to develop:
Wilms’ tumor
Aniridia
Genitourinary anomalies
mental Retardation
http://bms.brown.edu/pedisurg/images/ImageBank/Abdomen/WilmsCT8yo.jpg
WAGR
Aniridia
 Genitourinary Anomalies
 Mental Retardation

http://www.abdn.ac.uk/clsm/UserFiles/Image/collinson-eye-large.jpg
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

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
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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

Questions?
Bibliography
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Holger Scholz and Karin M. Kirschner, “A Role for the Wilms’
Tumor Protein WT1 in Organ Development,” Physiology 20: 5459 (2005)
Volkher Scharnhorst, et al., “WT1 proteins: functions in growth
and differentiation,” Gene 273: 141-161 (2001)
Kay-Dietrich Wagner, et al., “The complex life of WT1,” Journal
of Cell Science 116: 1653-1658 (2003)
Jordan A. Kreidberg, et al., “WT-1 is required for early liver
development,” Cell 74: 679-691 (1993)
National Cancer institute, “Wilms’ Tumor and Other Childhood
Kidney Tumors,” November 27, 2006.
<http://www.cancer.gov/cancertopics/pdq/treatment/wilms/Pati
ent>
International WAGR Syndrome Association, “What is WAGR
Syndrome?” Accessed April 27, 2007. <http://www.wagr.org/>
Monika L. Metzger, Jeffrey S. Dome., “Current Therapy for
Wilms’ Tumor,” Oncologist 10: 815-826 (2005)