The European renal genome project: an integrated approach towards understanding the genetics of kidney development and disease

Abstract

Rapid progress in genome research creates a wealth of information on the functional annotation of mammalian genome sequences. However, as we accumulate large amounts of scientific information we are facing problems of how to integrate and relate the data produced by various genomic approaches. Here, we propose the novel concept of an organ atlas where diverse data from expression maps to histological findings to mutant phenotypes can be queried, compared and visualized in the context of a three-dimensional reconstruction of the organ. We will seek proof of concept for the organ atlas by elucidating genetic pathways involved in development and pathophysiology of the kidney. Such a kidney atlas may provide a paradigm for a new systems-biology approach in functional genome research aimed at understanding the genetic bases of organ development, physiology and disease.

Keywords: EuReGene; development; genetics; genome; kidney; pathophysiology.

Figure 1

Development of the metanephros. This figure highlights the major steps in nephrogenesis starting with the formation, growth and branching of the ureteric bud from the Wolffian duct elicited by inductive signals from the metanephric blastema (A). In turn, signals originating from the tip of the ureter induce the metanephric mesenchyme to condense and undergo nephrogenesis (B). Finally, metanephric development proceeds through a complex series of morphogenic events including comma- and S-shaped body structures to give rise to the nephron and its specific components (C).

Figure 2

Structural and functional organization of the adult nephron. The nephron is organized in distinct structural elements (left panel) that are characterized by unique specialized cell types (middle panel), each of which performs specific tasks in volume and electrolyte homeostasis (right panel). For reasons of simplification, described activities of renal cell types focus on water and sodium chloride handling along the nephron segments, an activity that is central to the regulation of body volume and electrolyte balance, and to blood pressure regulation. (Figure adapted from, The Urinary System. In: Junqueira LC, Carneiro J, Kelley RO. Eds. Basic Histology. 8^th edition. Connecticut: Appleton & Lange,1995:369).

Figure 3

Optical projection tomography. Optical projection tomography (OPT) has been developed for 3D reconstruction of whole mount in situ or immunohistological analysis of early mouse embryos. (A). An E11.5 mouse embryo whole-mount stained for expression of the Sox9 gene (in which the staining is clearly visible, but determining exactly which tissues are expressing is not possible). (B) A 50-µm thick vibratome section cut through a similar whole-mount stained embryo, in which expression can be seen in several tissues. (C) The 3D OPT reconstruction of the embryo shown in (A). Virtual sections in three orthogonal planes are shown, within the context of the full 3D block of voxel data.

Figure 4

Three-dimensional reconstruction of glomeruli and vasculature in adult mouse kidneys. (A and B) OPT was used to reconstruct the 3D architecture of the glomeruli in the adult mouse kidney using lacZ staining in mice expressing the β-galactosidase gene in podocytes (A) or infusion of beads that are trapped in the glomeruli of normal mice (B). (C) OPT reconstruction of the vascular tree in the adult mouse kidney infused with molten latex. (Pictures courtesy of Jane Armstrong, University of Edinburgh and Annemieke IJpenberg, MRC, Edinburgh).

Figure 5

EuReGene kidney organ atlas. This figure represents an outline of the kidney organ atlas providing a unified graphical environment of the kidney architecture from 3D reconstructions and histological sections in which to visualize, query, and explore data generated from a variety of experimental approaches in renal development and (patho)physiology.