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PMID:7720589

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Citation

Ryan, G, Steele-Perkins, V, Morris, JF, Rauscher, FJ 3rd and Dressler, GR (1995) Repression of Pax-2 by WT1 during normal kidney development. Development 121:867-75

Abstract

The developmental, regulatory gene Pax-2 is activated during early kidney morphogenesis and repressed in mature renal epithelium. Persistent Pax-2 expression is also observed in a variety of kidney tumors. Yet, little is known about the signals regulating this transient expression pattern in the developing kidney. We have examined the spatial and temporal expression patterns of Pax-2 and the Wilm's tumor suppresser protein WT1 with specific antibodies in developing mouse kidneys. A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis. Furthermore, co-transfection assays using CAT reporter constructs under the control of Pax-2 regulatory sequences demonstrated WT1-dependent transcriptional repression. These three WT1 binding sites were also able to repress transcription, in a WT1-dependent manner, when inserted between a heterologous promoter and the reporter gene. The data indicate that Pax-2 is a likely target gene for WT1 and suggest a direct link, at the level of transcriptional regulation, between a developmental control gene, active in undifferentiated and proliferating cells, and a known tumor suppressor gene.

Links

PubMed

Keywords

Animals; Base Sequence; DNA-Binding Proteins/genetics; Gene Expression Regulation, Developmental; Genes, Regulator; Genetic Techniques; Kidney/embryology; Mice; Mice, Inbred Strains; Molecular Sequence Data; Morphogenesis/genetics; PAX2 Transcription Factor; Transcription Factors/genetics; WT1 Proteins; Zinc Fingers/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:WT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P32114

F

Seeded From UniProt

complete

HUMAN:WT1

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:WT1

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:EGR1

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PAX2

enables

GO:0070742: C2H2 zinc finger domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P19544

F

Seeded From UniProt

complete


See also

References

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