This applicant has proposed a program of research to prepare him for a career in basic science research in the field of BMP signaling and renal development/function. Research will be conducted in the laboratories of Dr. Herbert Lin and Dr. Dennis Brown at Massachusetts General Hospital. Reductions in branching morphogenesis and nephrogenesis (renal hypoplasia/dysplasia) result in renal failure or adult-onset hypertension. The cellular and molecular processes involved are poorly understood. Normal kidney development is dependent on mesenchymal-epithelial interactions in embryonic kidneys. Evidence suggests that BMP signaling is critically involved in these reciprocal inductive interactions. Dragon (RGMb) is a member of the three repulsive guidance molecule (RGM) family, which also includes RGMa and RGMc/HJV. We have recently identified the three RGM members to be the first known BMP co-receptors. We observed reduced branching of the ureteric bud (UB) at E13.5 and developmental defects in collecting ducts after birth in Dragon-null kidneys compared with the wild-type in mice. Our preliminary results also show that Dragon facilitates the use of BMP type II receptor ActIIA by BMP4 that otherwise prefers signaling via BMPRII. Interestingly, Dragon is highly expressed in ureteric branches and ActRIIA is the predominant BMP type II receptor in the bodies of ureteric branches, while BMP4 is expressed in mesenychymal cells surrounding the bodies of ureteric branches in early embryonic kidneys. In addition, Dragon is expressed in tubular epithelial cells and glomeruli in adult kidneys. We hypothesize that Dragon regulates renal branching morphogenesis by sensitizing UB epithelial cells to mesenchyme-derived BMP4 in early embryonic kidneys, and that inactivation of Dragon leads to disrupted mesenchyal-epithelial interactions, causing significant defects in renal development and function. Specifically, we will 1) determine the roles of Dragon and the underlying mechanisms in embryonic renal branching morphogenesis in vivo;2) determine the mechanisms of the action of Dragon in tubulogenesis in vitro;3) study the roles of Dragon in adult kidney functions using our Dragon knockout and kidney injury models. This work will shed light on the roles of Dragon in modulating BMP signaling in kidney development and function.
Embryonic kidney development requires bidirectional communication between ureteric bud/branches and surrounding mesenchyme cells. Currently, the molecular mechanisms of this communication are poorly understood. Emerging evidence suggests that the bone morphogenetic protein (BMP) system plays a critical role in this process. The work described here is aimed at proving that a protein called Dragon (also known as repulsive guidance molecule b, RGMb), a newly identified BMP co-receptor, regulates BMP signaling in ureteric branches by enhancing the utilization of BMP type II receptor ActRIIA by BMP4. This work, therefore, sets out to understand the mechanisms underlying the renal branching morphogenesis that is necessary for normal kidney function. We hope to identify new protein targets for development of methods to better manage renal hypoplasia and dysplasia.
| Xia, Yin; Cortez-Retamozo, Virna; Niederkofler, Vera et al. (2011) Dragon (repulsive guidance molecule b) inhibits IL-6 expression in macrophages. J Immunol 186:1369-76 |
