Cell and molecular biology of kidney development

Abstract

Abnormalities of kidney and urinary tract development are the most common cause of end-stage kidney failure in childhood in the United States. Over the past 20 years, the advent of mutant and transgenic mice and the manipulation of gene expression in other animal models has resulted in major advances in identification of the cellular and molecular mechanisms that direct kidney morphogenesis, providing insights into the pathophysiology of renal and urologic anomalies. This review focuses on the molecular mechanisms that define kidney progenitor cell populations, induce nephron formation within the metanephric mesenchyme, initiate and organize ureteric bud branching, and participate in terminal differentiation of the nephron. Highlighted are common signaling pathways that function at multiple stages during kidney development, including signaling via Wnts, bone morphogenic proteins, fibroblast growth factor, sonic hedgehog, RET/glial cell-derived neurotrophic factor, and notch pathways. Also emphasized are the roles of transcription factors Odd1, Eya1, Pax2, Lim1, and WT-1 in directing renal development. Areas requiring future investigation include the factors that modulate signaling pathways to provide temporal and site-specific effects. The evolution of our understanding of the cellular and molecular mechanisms of kidney development may provide methods for improved diagnosis of renal anomalies and, hopefully, targets for intervention for this common cause of childhood end-stage kidney disease.

Figure 1

(A) schema of metanephric kidney development: The ureteric bud (UB) arises from the Wolfian duct (part of the mesonephros) at embryonic day 9 (E9) in mice. Nephrons are induced at tips of the ureteric bud branches; the serial branching of the ureteric bud establishes the radial structure of the kidney architecture. Wnt signals provide the major signal for induction, stimulating aggregation of metanephric mesenchymal (MM) cells and transformation to an epithelial cell phenotype (MET). The epithelial cells form a vesicle, then comma and S-shaped body. Notch2 defines cell fate of the proximal segments of the S-shaped body, the future podocytes and proximal tubule, while the distal segment form the distal tubule. By E14.5, the first glomeruli are formed, with podocytes with foot processes, slit diaphragms, glomerular basement membrane (GBM) and a fenestrated endothelium (EC). (B) PAS of newborn mouse kidney exhibiting developing nephrons (ureteric bud (UB) and renal vesicles (V)) in the outer nephrogenic cortex, and a mature glomeruli (G) in the deep cortex.

Figure 2

Hierarchy of transcription factors in nephron progenitor cells

Figure 3

Schema of major signaling pathways involved in renal development (for space and clarity, not all factors in each pathway shown)

Figure 4

Crosstalk between sonic hedgehog (Shh), bone morphogenic protein (BMP), fibroblast growth factor (FGF) and GDNF/ret signaling pathways modulates ureteric bud branching