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Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities
G R Dressler1, J E Wilkinson, U W Rothenpieler
1Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
Abstract:
The Pax genes comprise a family of transcription factors active in specific tissues during embryonic development and are associated with at least three developmental mutations in mouse and man. In the developing kidney, Pax-2 is expressed in the induced mesenchyme, in the ureter epithelium, and in early epithelial structures derived from the mesenchyme. Pax-2 expression is repressed upon terminal differentiation of the renal tubule epithelium, but persists in the undifferentiated epithelium of human Wilms' tumours. We have produced a dominant gain-of-function mutation in transgenic mice by deregulating the expression of the mouse Pax-2 gene. The data obtained with four independently derived transgenic embryos and with one transgenic line demonstrate that deregulated Pax-2 expression results in histologically abnormal and dysfunctional renal epithelium with properties similar to congenital nephrotic syndrome. Thus, repression of Pax-2 is required for normal kidney development and persistent expression of Pax-2 may restrict the differentiation potential of renal epithelial cells.
Insights
Repressing Pax-2 is crucial for normal kidney development. Deregulated Pax-2 expression in mice leads to abnormal renal epithelium, mimicking congenital nephrotic syndrome.
Area of Science:
- Developmental biology
- Genetics
- Nephrology
Background:
- Pax genes are transcription factors vital for embryonic development.
- Pax-2 is expressed in developing kidney tissues and is implicated in Wilms' tumors.
- Normal kidney development requires repression of Pax-2 expression.
Purpose of the Study:
- To investigate the role of Pax-2 in kidney development.
- To determine the consequences of deregulated Pax-2 expression in vivo.
- To explore the link between Pax-2 and congenital nephrotic syndrome.
Main Methods:
- Generated a dominant gain-of-function mutation in transgenic mice by deregulating mouse Pax-2 gene expression.
- Analyzed four independently derived transgenic embryos and one transgenic line.
- Examined renal epithelium histology and function.
Main Results:
- Deregulated Pax-2 expression resulted in histologically abnormal and dysfunctional renal epithelium.
- The observed renal abnormalities were similar to those seen in congenital nephrotic syndrome.
- Persistent Pax-2 expression was linked to restricted differentiation potential in renal epithelial cells.
Conclusions:
- Repression of Pax-2 is essential for normal kidney development.
- Persistent Pax-2 expression can impair renal epithelial cell differentiation.
- Deregulated Pax-2 may contribute to developmental kidney diseases like congenital nephrotic syndrome.