title: Genes and proteins in renal development.
abstract: Metanephric kidney development begins with the formation of the metanephrogenic mesenchyme; this event depends on the prior action in the intermediate mesoderm of transcription factors such as Lim-1, Pax-2, Eya-1, and Foxc-1. Once it has formed, the mesenchyme secretes GDNF; this induces the nearby wolffian duct to produce a ureteric bud which invades the metanephrogenic mesenchyme and begins to arborize. Ureteric bud development and branching depends on the transcription factor Emx-2, the GDNF-cRet and probably the HGF/cMet, signalling systems, and the intracellular regulatory molecules formin IV and timeless. Proteins of the BMP family modulate ureteric bud branching and keep bud development in step with that of other tissue types. Proteins and glycosaminoglycans of the matrix, and their receptors, and also required. The metanephrogenic mesenchyme has a default fate of apoptosis and is dissuaded from suicide by factors secreted from the bud such as TGF-alpha, TIMP-2, EGF, and FGF-2. Other factors such as LIF and TGFbeta2 cooperate with these to induce clumps of mesenchyme cells to differentiate into nephrons, while BMP-7 appears to lead them instead to form stroma. As nephrons form, they express critical transcription factors such as WT-1, Pax-2, and Hoxa11 and d11, condense, and secrete Wnt-4. Wnt-4 acts in an autocrine loop to stimulate its own synthesis and is required for cells to differentiate into epithelia; its action is antagonized by sFRP-1, secreted by stroma, but this antagonism is itself inhibited by sFRP-2 made by the developing nephron. This system probably acts both to limit the spread of Wnt-4's influence and also to commit responding cells to their epithelial fate. As nephrons mature, regions of them differentiate to perform specific physiological functions, a process that requires the proteins WT-1, Lmx-1b, Notch-2, Jagged-1, and Hnf-1.
authors.affiliation: Centre for Developmental Biology, Edinburgh University Medical School, Teviot Place, Edinburgh EH8 9AG, UK. Jamie.Davies@ed.ac.uk
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Davies
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Fisher
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000235:genetics; D029721:Drosophila Proteins; D005346:Fibroblast Growth Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D016023:Integrins / Q000235:genetics; D007668:Kidney / Q000196:embryology* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D016023:Integrins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D005346:Fibroblast Growth Factors; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila