Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis

Charles E Patek; Stewart Fleming; Colin G Miles; Christopher O Bellamy; Michael Ladomery; Lee Spraggon; John Mullins; Nicholas D Hastie; Martin L Hooper

doi:10.1093/hmg/ddg240

Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis

Charles E Patek, Stewart Fleming, Colin G Miles, Christopher O Bellamy, Michael Ladomery, Lee Spraggon, John Mullins, Nicholas D Hastie, Martin L Hooper

Research output: Contribution to journal › Article › peer-review

Abstract

Denys-Drash syndrome (DDS) is caused by dominant mutations of the Wilms' tumour suppressor gene, WT1, and characterized by a nephropathy involving diffuse mesangial sclerosis, male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that heterozygosity for the Wt1tmT396 mutation induces DDS in heterozygous and chimeric (Wt1tmT396/++/+) mice. In the present study, the fate of Wt1 mutant cells in chimeric kidneys was assessed by in situ marker analysis, and immunocytochemistry was used to re-examine the claim that glomerulosclerosis (GS) is caused by loss of WT1 and persistent Pax-2 expression by podocytes. Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of GS was preceded by widespread loss of ZO-1 signal in podocytes (even in kidneys where

Original language	English
Pages (from-to)	2379-94
Number of pages	16
Journal	Human Molecular Genetics
Volume	12
Issue number	18
DOIs	https://doi.org/10.1093/hmg/ddg240
Publication status	Published - 15 Sep 2003

Keywords

Animals
Cell Differentiation
DNA
Denys-Drash Syndrome
Gene Expression
Genes, Dominant
Genes, Tumor Suppressor
Genetic Markers
Glomerulonephritis
Glucose-6-Phosphate Isomerase
Heterozygote
Immunohistochemistry
In Situ Hybridization
Kidney Glomerulus
Membrane Proteins
Mice
Mice, Knockout
Mutation
Phosphoproteins
Renin
Transforming Growth Factor beta
Transforming Growth Factor beta1
WT1 Proteins
Zonula Occludens-1 Protein

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title = "Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis",

abstract = "Denys-Drash syndrome (DDS) is caused by dominant mutations of the Wilms' tumour suppressor gene, WT1, and characterized by a nephropathy involving diffuse mesangial sclerosis, male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that heterozygosity for the Wt1tmT396 mutation induces DDS in heterozygous and chimeric (Wt1tmT396/++/+) mice. In the present study, the fate of Wt1 mutant cells in chimeric kidneys was assessed by in situ marker analysis, and immunocytochemistry was used to re-examine the claim that glomerulosclerosis (GS) is caused by loss of WT1 and persistent Pax-2 expression by podocytes. Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of GS was preceded by widespread loss of ZO-1 signal in podocytes (even in kidneys where ",

keywords = "Animals, Cell Differentiation, DNA, Denys-Drash Syndrome, Gene Expression, Genes, Dominant, Genes, Tumor Suppressor, Genetic Markers, Glomerulonephritis, Glucose-6-Phosphate Isomerase, Heterozygote, Immunohistochemistry, In Situ Hybridization, Kidney Glomerulus, Membrane Proteins, Mice, Mice, Knockout, Mutation, Phosphoproteins, Renin, Transforming Growth Factor beta, Transforming Growth Factor beta1, WT1 Proteins, Zonula Occludens-1 Protein",

author = "Patek, {Charles E} and Stewart Fleming and Miles, {Colin G} and Bellamy, {Christopher O} and Michael Ladomery and Lee Spraggon and John Mullins and Hastie, {Nicholas D} and Hooper, {Martin L}",

year = "2003",

month = sep,

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doi = "10.1093/hmg/ddg240",

language = "English",

volume = "12",

pages = "2379--94",

journal = "Human Molecular Genetics",

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T2 - evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis

AU - Patek, Charles E

AU - Fleming, Stewart

AU - Miles, Colin G

AU - Bellamy, Christopher O

AU - Ladomery, Michael

AU - Spraggon, Lee

AU - Mullins, John

AU - Hastie, Nicholas D

AU - Hooper, Martin L

PY - 2003/9/15

Y1 - 2003/9/15

N2 - Denys-Drash syndrome (DDS) is caused by dominant mutations of the Wilms' tumour suppressor gene, WT1, and characterized by a nephropathy involving diffuse mesangial sclerosis, male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that heterozygosity for the Wt1tmT396 mutation induces DDS in heterozygous and chimeric (Wt1tmT396/++/+) mice. In the present study, the fate of Wt1 mutant cells in chimeric kidneys was assessed by in situ marker analysis, and immunocytochemistry was used to re-examine the claim that glomerulosclerosis (GS) is caused by loss of WT1 and persistent Pax-2 expression by podocytes. Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of GS was preceded by widespread loss of ZO-1 signal in podocytes (even in kidneys where

AB - Denys-Drash syndrome (DDS) is caused by dominant mutations of the Wilms' tumour suppressor gene, WT1, and characterized by a nephropathy involving diffuse mesangial sclerosis, male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that heterozygosity for the Wt1tmT396 mutation induces DDS in heterozygous and chimeric (Wt1tmT396/++/+) mice. In the present study, the fate of Wt1 mutant cells in chimeric kidneys was assessed by in situ marker analysis, and immunocytochemistry was used to re-examine the claim that glomerulosclerosis (GS) is caused by loss of WT1 and persistent Pax-2 expression by podocytes. Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of GS was preceded by widespread loss of ZO-1 signal in podocytes (even in kidneys where

KW - Animals

KW - Cell Differentiation

KW - DNA

KW - Denys-Drash Syndrome

KW - Gene Expression

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KW - Genes, Tumor Suppressor

KW - Genetic Markers

KW - Glomerulonephritis

KW - Glucose-6-Phosphate Isomerase

KW - Heterozygote

KW - Immunohistochemistry

KW - In Situ Hybridization

KW - Kidney Glomerulus

KW - Membrane Proteins

KW - Mice

KW - Mice, Knockout

KW - Mutation

KW - Phosphoproteins

KW - Renin

KW - Transforming Growth Factor beta

KW - Transforming Growth Factor beta1

KW - WT1 Proteins

KW - Zonula Occludens-1 Protein

U2 - 10.1093/hmg/ddg240

DO - 10.1093/hmg/ddg240

M3 - Article

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JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 18

ER -

Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis

Abstract

Keywords

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