Normal kidney development is essential to ensure proper function of the mature kidney. A crucial step in mammalian kidney development is the regulation of ureteric bud (UB) branching morphogenesis. Bone morphogenetic proteins (BMPs) are important signaling molecules required for kidney development, but the precise functions of individual BMP ligands remain poorly understood (Cain 2008;Blank 2008). Kidneys of BMP4 null heterozygote mice showed slower growth and branching of ureteric buds (Miyazaki 2000, Hartwig 2005). In humans, mutations in the BMP4 gene are associated with anomalous kidney development (Weber 2008). BMP4 normally utilizes BMPRII and not ActRIIA for signaling. BMP4 is expressed in the mesenchyme adjacent to the bodies of ureteric branches, but not in the ureteric bud itself. Surprisingly, ActRIIA, and not BMPRII, is the predominant BMP type II receptor found in the bodies of ureteric branches, thus providing a puzzle as to how BMP4 from the mesenchyme can efficiently signal in UB cells. In the prior funding period, we discovered a GPI-anchored protein named Dragon, and showed that it functions as a BMP co-receptor (Samad 2005) and is widely expressed in tubular epithelial cells of the adult kidney (Xia et al JASN 2010). Importantly, we showed that the presence of Dragon allows BMP4 to gain the ability to signal via ActRIIA. Here, we present preliminary data that Dragon is highly expressed in epithelial cells of ureteric branches in the embryonic kidney, and that Dragon null embryonic kidneys at E13.5 showed significant decreases in ureteric branching compared to wild-type kidneys. We hypothesize that Dragon plays an important role in the communication between mesenchymal and ureteric epithelial cells by facilitating mesenchymal BMP4 signaling through ActRIIA in ureteric bud epithelial cells. The biochemical mechanisms of action of Dragon in BMP4 signaling will be studied in Specific Aim I. The role of Dragon during kidney development will be determined by analyzing Dragon null embryonic metanephros in Specific Aim II. Completion of the proposed studies will enhance our understanding of the regulation of BMP signaling, and provide clues to their crucial roles during kidney development.
Reductions in branching morphogenesis and nephrogenesis (renal hypodysplasia) result in abnormal renal architecture and in renal failure and adult-onset hypertension. The cellular and molecular processes involved are poorly understood, but abundant evidence suggests that bone morphogenetic (BMP) signaling is critically involved. We will study the role of the BMP co-receptor Dragon in BMP signaling in kidney development and function.
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