Comparative analysis of osr1 function in nephrogenesis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Odd-skipped related 1 (osr1) is the earliest gene known to be expressed during the formation of the intermediate mesoderm (IM), the embryonic tissue which gives rise to all vertebrate kidney tissue. In zebrafish, chicken, and mouse embryos, osr1 is expressed in undifferentiated IM, and is down regulated upon initiation of kidney duct and tubule formation. Injection of morpholinos to osr1 in zebrafish leads to almost complete loss of early kidney markers, expansion of both dorsal and ventral markers, and a hyperconvergent extension phenotype similar to the Bmp2b mutant swirl. Mice with homozygous deletions in osr1 have severe defects in kidney formation. Misexpression of osr1 in chicken embryos results in ectopic expression of kidney genes in the somite. Finally, osr1 expression is lost in zebrafish swirl mutants. From these data, several, not mutually exclusive hypotheses regarding the function and regulation of osr1 during kidney formation can be postulated: (1) osr1 functions during early embryonic patterning to inhibit dorsal and ventral patterning and establish a band of tissue competent to form IM; (2) osr1 directly promotes early kidney gene expression; and (3) osr1 maintains kidney precursor cells in an early lineage compartment and inhibits terminal differentiation of epithelial structures. These hypothesis will be tested by conducting osr1 gain and loss of function experiments in zebrafish, chicken, and mouse embryos, by studying the effects of the misexpression of other kidney regulatory genes on osr1 expression, and by examining osr1 expression in zebrafish dorso-ventral patterning mutants. By studying osr1 in three diverse vertebrate embryos, a comprehensive picture should emerge of the roles of osr1 during kidney formation, which should add significantly to our understanding of the regulation of kidney development. The studies may also lead to increased understanding of congenital kidney anomalies and may yield important information that can be used to generate kidney tissue for therapeutic purposes.