Cell
Volume 74, Issue 4, 27 August 1993, Pages 679-691
Journal home page for Cell

Article
WT-1 is required for early kidney development

https://doi.org/10.1016/0092-8674(93)90515-RGet rights and content

Abstract

In humans, germline mutations of the WT-1 tumor suppressor gene are associated with both Wilms' tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital development, we introduced a mutation into the murine WT-1 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. Our results establish a crucial role for WT-1 in early urogenital development.

References (52)

  • V.P. Sukhatme

    The Egr transcription factor family: from signal transduction to kidney differentiation

    Kidney Int.

    (1992)
  • K.R. Thomas et al.

    Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells

    Cell

    (1987)
  • C.C.T. Ton et al.

    Smallest region of overlap in Wilms' tumor deletions uniquely implicates an 11p13 zinc finger gene as the disease locus

    Genomics

    (1991)
  • A. Weller et al.

    Development and growth of mouse embryonic kidney in organ culture and modulation of development by soluble growth factor

    Dev. Biol.

    (1991)
  • Z.Y. Wang et al.

    The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene

    J. Biol. Chem.

    (1992)
  • J.F. Armstrong et al.

    The expression of the Wilms' tumor gene, WT-1, in the developing mammalian embryo

    Mech. Dev.

    (1992)
  • P.N. Baird et al.

    Identification of mutations in the WT1 gene in tumours from patients with the WAGR syndrome

    Oncogene

    (1992)
  • W.A. Bickmore et al.

    Modulation of DNA binding specificity by alternative splicing of the Wilms' tumor WT1 gene transcript

    Science

    (1992)
  • A. Bradley

    Production and Analysis of Chimeric Mice

  • W. Bruening et al.

    Germline intronic and exonic mutations in the Wilms' tumor gene (WT1) affecting urogenital development

    Nature Genet.

    (1992)
  • A.J. Buckler et al.

    Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development

    Mol. Cell. Biol.

    (1991)
  • A.R. Clarke et al.

    Requirement for a functional Rb-1 gene in murine development

    Nature

    (1992)
  • J.K. Cowell et al.

    Structural rearrangements of the WT1 gene in Wilms' tumour cells

    Oncogene

    (1991)
  • Y. Croisille

    On some recent contributions to the study of kidney tubulogenesis in mammals and birds

  • T.C. Doetschman et al.

    The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium

    J. Embryol. Exp. Morphol.

    (1985)
  • G.R. Dressler et al.

    Pax-2 is a DNA-binding protein expressed in embryonic kidney and Wilms' tumor

  • Cited by (0)

    ā€”

    Present address: Nichirei Corporation, 1-52-14, Kumegawa-cho, Higashimurayama-shi, Tokyo, Japan.

    View full text