Project 3 Canonical Wnt regulation of renal interstitium fate and function

University Of Virginia, Charlottesville VA

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Abstract

The embryonic renal interstitium plays critical regulatory roles in renal development. However, our knowledge of its cellular composition, the functions of its individual cellular constituents, and the full scope of its involvement in renal formation and function is far from complete. We found that in the deeper cortex (excluding the part of the cortex from the surface of the kidney to where S-shaped bodies locate) and medulla, the response of Wnt/p-catenin signaling in the embryonic renal interstitium is confined to about two layers of cells adjacent to ureteric trunks (Wnt/p-catenin target cells), and the expression of certain genes in these cells were disrupted when (3-catenin was ablated specifically from the renal interstitium. The overall objective of this proposal is to test the hypothesis the HDACl/2 inhibit epigenetically Wnt/(3-catenin signaling which regulates the fate of it target renal interstitial cells and their function in regulating kidney development. Specifically, using a combination of mouse genetics, biochemical and molecular biology, we will determine the identity ofthe interstitial cells that do and do not respond to Wnt/p-catenin signaling during normal development and their fates in response to ablation of Wnt/p-catenin signaling (Aimi). Further, we will test the hypothesis that the Wnt/p-catenin signaling target interstitial cells affect the proper formation of loop-of- Henle and microvascular endothelium in the developing kidney (Aim2). HDAC1 and HDAC2, histone deacetylases that remove acetyl groups from either core histones or non-histone proteins, function in either an epigenetic or a non-epigenetic manner. In specific Aim 3, we will test the hypothesis that HDACl/2 inhibits Wnt/p-catenin signaling in the renal interstitium epigenetically. The proposed work will significantly expand our mechanistic understanding ofthe regulation of renal interstitial cell fates, and uncover additional functions of the renal interstitium during kidney development. Further, it will define the cellular composition of the majority ofthe renal interstitium which will facilitate future work of targeted manipulation ofthe renal interstitium to reveal additional functions ofthe renal interstitium. The knowledge and information acquired from the proposed research will also assist diagnosis and treatment of congenital renal diseases in children.