All vertebrate kidney tissue is derived from the intermediate mesoderm (IM), a strip of tissue that lies between the somites and the lateral plate in the developing embiyo. Although much progress has been made in understanding later stages of kidney development, during which the IM differentiates into kidney tubules, very little is known about the critical, early stages in which the IM itself is generated. The proposed studies investigate the embryological mechanisms which regulate IM formation in the avian embryo. The avian embryo is used because it can be experimentally manipulated throughout the process of IM formation, allowing a broad range of in vivo and in vitro studies to be performed. In the first part of the proposal, a range of in vivo and in vivo experimental manipulations will be performed to identify the embryonic tissues that are the sources of signals that pattern the IM. In the second part, the role in IM specification of one such signal, Retinoic Acid (RA), will be investigated. A line of Vitamin A deficient (VAD) quails, which are deficient in RA signaling, will be used to determine the dependence of IM development on RA signaling. The effects of ectopically applied RA and RA antagonists on IM gene expression will also be studied. Finally, the role of Hox genes, a potential target of RA signaling, in regulating the formation of the anterior border of the IM will be investigated using targeted gene misexpression via an avian retrovirus. Kidney disease is a leading cause of morbidity and mortality in the United States. One potential treatment approach to kidney disease is to supplement kidney function with grafts of kidney tissue that have been generated in the laboratory. Efforts to generate kidney tissue in vitro would be greatly facilitated by knowledge of how kidney tissue is generated in vivo, in the developing embryo. The current experiments directly tackle this problem by attempting to uncover the signaling events that regulate IM formation. The experiments with RA (Aim 2) should be directly relevant to efforts to generate IM in vitro, while the experiments of the first part of the proposal will lay the groundwork for future experiments aimed at identifying other molecular mediators of IM formation. In addition, congenital defects of the nephric system are one of the most common types of birth defects in humans, and Vitamin A deficiency is a known cause of congenital kidney disease. The experiments in the second part of this proposal may shed light on the embryological mechanisms underlying a portion of the cases of congenital nephric system malformations.
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