Kidney development: from ureteric bud formation to branching morphogenesis

Abstract

Epithelial branching morphogenesis is critical to the formation of various organs such as the vasculature, mammary glands, lungs, and kidneys in vertebrate embryos. One fascinating aspect of branching morphogenesis is to understand how a simple epithelial tube grows by reiterative branching to form a complex epithelial tree structure. Recent studies combining mouse genetics and chimeric analysis with live imaging have uncovered the molecular networks and interactions that govern kidney branching morphogenesis. This review focuses on ureteric bud (UB) formation and epithelial branching during kidney development. The invasion of the metanephric mesenchyme by the UB is a fundamental step toward establishing the cyto-architecture of the kidney and determining the number of nephrons, which form the filtration units of the adult kidney.

Figure 1. Cell movements and heterogeneous Ret signaling during ureteric bud formation

Diagram illustrating rearrangement of Ret “positive” (blue) and Ret “negative” cells (green). Gray ovals represent the metanephric mesenchyme. Initially Ret “positive” cells are dispersed along the WD (A) and start to move (yellow arrows) to form the primary ureteric bud (UB) tip domain (B). As the UB grows out, these cells “lead” to form the distal tip, while Ret “negative” cells follow (C, red arrows). Reproduced with permission from [25]

Figure 2. Molecular interactions of the signals and antagonists participating in kidney epithelial branching morphogenesis

The Ret/GDNF pathway is restricted to the tip of the developing UB epithelium to insure progression of branching morphogenesis. Correct activity of Ret is assured by positive (Wnt11) and negative (Sprouty1) feedback signaling. Other RTK signal pathways such as FGF, EGF and HGF also positively contribute to this feedback loop. Along the ureteric stalk, BMP4 signaling exerts an inhibitory effect on branching morphogenesis. Inhibition of BMP4 by Gremlin 1 in the mesenchyme surrounding the UB tip region could enables branching morphogenesis.

Figure 3. In vivo visualization of UB branching morphogenesis

(A) A metanephric kidney rudiment (E12.5) cultured on a Transwell filter at the air/surface interface at 37°C for 48 hours. The epithelium is marked by GFP expression using the HoxB7-mVenus transgene [52]. (B) The epithelial branching tree visualized in an E15.0 kidney by confocal microscopy to reveal the complex 3D architecture of the UB tree.