Anat Cell Biol.  2013 Mar;46(1):19-31. 10.5115/acb.2013.46.1.19.

Molecular regulation of kidney development

• Chai OH
• Song CH
• Park SK
• Kim W
• Cho ES

• KMID: 2046754
• DOI: http://doi.org/10.5115/acb.2013.46.1.19

Abstract

Genetically engineered mice have provided much information about gene function in the field of developmental biology. Recently, conditional gene targeting using the Cre/loxP system has been developed to control the cell type and timing of the target gene expression. The increase in number of kidney-specific Cre mice allows for the analysis of phenotypes that cannot be addressed by conventional gene targeting. The mammalian kidney is a vital organ that plays a critical homeostatic role in the regulation of body fluid composition and excretion of waste products. The interactions between epithelial and mesenchymal cells are very critical events in the field of developmental biology, especially renal development. Kidney development is a complex process, requiring inductive interactions between epithelial and mesenchymal cells that eventually lead to the growth and differentiation of multiple highly specialized stromal, vascular, and epithelial cell types. Through the use of genetically engineered mouse models, the molecular bases for many of the events in the developing kidney have been identified. Defective morphogenesis may result in clinical phenotypes that range from complete renal agenesis to diseases such as hypertension that exist in the setting of grossly normal kidneys. In this review, we focus on the growth and transcription factors that define kidney progenitor cell populations, initiate ureteric bud branching, induce nephron formation within the metanephric mesenchyme, and differentiate stromal and vascular progenitors in the metanephric mesenchyme.

Keyword

Cre/loxP system; Kidney; Development; Metanephric mesenchyme; Ureteric bud

MeSH Terms

Animals
Body Fluids
Congenital Abnormalities
Developmental Biology
Epithelial Cells
Gene Expression
Gene Targeting
Hypertension
Kidney
Kidney Diseases
Mesoderm
Mice
Morphogenesis
Nephrons
Phenotype
Stem Cells
Transcription Factors
Ureter
Waste Products
Congenital Abnormalities
Kidney
Kidney Diseases
Transcription Factors
Waste Products

Figure

• 

  Fig. 1 Kidney-specific Cre/loxP recombination. Cre recombinase is expressed under the control of a kidney-specific promoter (left), and two loxP sites are inserted in the introns flanking an essential exon of a gene of interest (right). In the kidney, Cre recombinase will be expressed and will excise the DNA sequence between the loxP sites, which will inactivate the gene. In all other tissues, Cre will not be expressed and the gene will remain active.

• 

  Fig. 2 Scheme of renal developmental processes. Kidney organogenesis depends on a series of reciprocal inductive interactions between the ureteric bud (UB) and metanephric mesenchyme (MM). Signals from the MM initiate kidney development by inducing formation of the UB from the Wolffian duct. The UB invades the MM and undergoes a series of repetitive branchings under the influence of mesenchymal signals. In turn, the newly formed UB induces the MM that surrounds it to condense around its tips. The condensed mesenchyme (CM) successively differentiates into pre-tubular aggregates, and these structures undergo a mesenchymal-to-epithelial transition (MET) to form renal vesicles (RVs), which then proliferate to give rise to comma- and S-shaped bodies, and then nephrons. Parallel to this differentiation process, the distal part of the S-shaped bodies fuses with collecting ducts, and the proximal parts of these structures become highly vascularized and form glomeruli.

• 

  Fig. 3 Time course of renal morphogenesis in wild-type mice. Kidneys from E10.5 (A), E12.5 (B), and E15.5 (C) embryos, and P0 (D) mouse were stained with hematoxylin and eosin. The ureteric bud (UB) is derived from the Wolffian duct (WD), and the metanephric mesenchyme (MM) is formed from the intermediate mesoderm. The condensed mesenchyme (CM) successively differentiates into the renal vesicle, which then proliferates to give rise to comma- and S-shaped bodies and glomeruli (G). Scale bar in (A)=50 µm (A.D).

• 

  Fig. 4 Molecular signaling pathways involved in ureteric bud outgrowth and branching (A), mesenchymal-to-epithelial transition (MET) (B), and nephron patterning (C). (A) Molecules and growth factors (Gdnf and Fgfs) from the adjacent cells of the metanephric mesenchyme bind to a variety of receptor-tyrosine kinases (Ret and Fgfr) on the surface of the ureteric tip cell, triggering signaling cascades that regulate cell proliferation, migration, and extracellular matrix degradation. The combined actions of these signaling pathways are continued branching and elongation of the ureteric epithelium to form the collecting duct system. (B) Just as Gdnf/Ret signaling has been central to branching, Wnt signaling is key to kidney development, with both Wnt4 and Wnt9b being involved in MET. In addition to Wnt, Fgfs, Wt1, and Odd1, there are other factors required for MET. Fgf8 is ex pressed earlier than Wnt4 and is ne cessary for both Wnt4 and Lim1. A tripartite complex between Eya1, Pax2, and Hox11 positively regulates the expression of Gdnf and Six2. (C) The transcriptional hierarchy of genes governing nephron pattering is shown. Wnt9b initially activates the expression of Fgf8, Wnt4, and Pax8 in the pre-tubular aggregate (PA), and then Wnt4 maintains the expression of these genes and induces Lim1. Wt1 is restricted to the proximal S-shaped body (SB) and maintained in the podocytes throughout all stages of nephrogenesis. Notch2 is required in the patterning of the pro ximal nephron. In addition, Megalin, Umo, integrin α3/β1, and Nphs play critical roles in the patterning of the loop of Henle (LH), distal tubule (DT), and the formation of functional filters. CB, comma-shaped body; PC, podocyte cells; PT, proximal tubule; RV, renal vesicle; UB, ureteric bud.

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