Fox genes in urinary tract development

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Inherited disorders of the kidney and urinary tract are quite common in humans, but their etiology and underlying developmental mechanisms are poorly understood. It is clear that animal models need to be characterized to elucidate the molecular and cellular mechanisms of congenital obstruction of the urinary tract. Mutant mice provide useful models to address the many unresolved questions about congenital urinary tract obstruction, and recent studies have suggested that the impairment of embryonic steps, the ureteric budding and differentiation of smooth muscle around the ureter, leads to urinary tract abnormalities such as hydroureter and hydronephrosis. Foxc1 and Foxc2 encode forkhead/Fox transcription factors with virtually identical DNA binding domains and overlapping expression patterns in various embryonic tissues, including the intermediate mesoderm, metanephric mesenchyme, and smooth muscle progenitors surrounding the ureter. We have previously shown that depending on the genetic background most Foxc1 homozygous mutants are born with abnormalities of he metanephric kidney, including duplex kidneys, and double ureters, one of which is hydroureter. Most importantly, Foxc1 homozygotes have an ectopic anterior ureteric bud. These findings support the hypothesis of Mackie and Stephens concerning the etiology of duplex kidney and hydroureter in human infants with congenital kidney abnormalities. Interestingly, most compound Foxc1; Foxc2 heterozygotes have hypoplastic kidneys and a single hydroureter although they have double ureteric buds, suggesting that the two genes functionally interact in kidney and urinary tract development. Expression of Foxd2, another related Fox gene, overlaps with that of Foxc1 and Foxc2 in the developing kidney and urinary tract. We have also shown that Foxd2 mutant mice have similar defects such as hydroureter, and recent analysis of compound Foxc1; Foxd2 ihomozygotes revealed a functional overlap between the two genes in ureter morphogenesis. The results of all of this work lead to the central hypothesis that three Fox transcription factors play cooperative roles in the steps of the ureteric budding and smooth muscle differentiation surrounding the ureter. This hypothesis will be tested by: (1) analysis of functional domains in three Fox protein's (Foxc1, Foxc2, and Foxd2), (2) analysis of the formation and growth of the ureteric bud in compound Fox mutant embryos, (3) analysis of the development of smooth muscle surrounding the ureter in compound Fox mutant embryos. These studies will significantly contribute to a better understanding of the etiology of congenital urinary tract obstruction in infants and children and gain insight into the cellular and molecular basis of human abnormalities.