Human Molecular Genetics Advance Access published online on September 11, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn297
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Fras1, a basement membrane-associated protein mutated in Fraser syndrome, mediates both the initiation of the mammalian kidney and the integrity of renal glomeruli
1 Nephro-Urology, UCL Institute of Child Health, London WC1N 1EH, UK 2 Molecular Medicine Units, UCL Institute of Child Health, London WC1N 1EH, UK
* Correspondence to Adrian S. Woolf, Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Phone: 00 44 20 7905 2615. Fax 00 44 20 7905 2133. Email a.woolf{at}ich.ucl.ac.uk
Received August 7, 2008; Revised September 10, 2008; Accepted September 10, 2008
FRAS1 is mutated in some individuals with Fraser syndrome and the encoded protein is expressed in embryonic epidermal cells, localising in their basement membrane. Syndactyly and cryptophthalmos in Fraser syndrome are sequelae of skin fragility but the bases for associated kidney malformations are unclear. We demonstrate that Fras1 is expressed in the branching ureteric bud, and that renal agenesis occurs in homozygous Fras1 null mutant blebbed (bl) mice on a C57BL6J background. In vivo, the bl/bl bud fails to invade metanephric mesenchyme which undergoes involution, events replicated in organ culture. Expression of Gdnf and Gdf11 was defective in bl/bl renal primordia in vivo whereas, in culture, addition of either growth factor restored bud invasion into the mesenchyme. Mutant primordia also showed deficient expression of Hoxd11 and Six2 transcription factors whereas activity of Bmp4, an anti-branching molecule, was upregulated. In wild-types, Fras1 was also expressed by nascent nephrons. Fetal glomerular podocytes expressed Fras1 transcripts and Fras1 immunolocalised in a glomerular basement membrane-like pattern. On a mixed background, bl mutants, and also compound mutants for bl and my, another bleb strain, sometimes survive into adulthood. These mice have two kidneys which contain subsets of glomeruli with perturbed nephrin, podocin, integrin 
3 and fibronectin expression. Thus, Fras1 protein coats branching ureteric bud epithelia and is strikingly upregulated in the nephron lineage after mesenchymal/epithelial transition. Fras1 deficiency causes defective interactions between the bud and mesenchyme, correlating with disturbed expression of key nephrogenic molecules. Furthermore, Fras1 may also be required for formation of normal glomeruli.