BMPs and BMP receptors in mouse metanephric development: in vivo and in vitro studies

BMPs have recently emerged as likely regulators of development of the permanent kidney (metanephros). Transcripts for BMPs and their receptors have been localised in the developing metanephros. In vitro, BMPs 2, 4 and 7 have direct or indirect roles in regulation of ureteric branching morphogenesis and branch formation. In vivo, renal phenotypes have been reported in BMP7 homozygous null mutant mice and BMP4 heterozygous null mutant mice. In the present study, in vivo and in vitro roles of BMPs and BMP receptors in metanephric development were further analysed. Stereology and histology were used to analyse kidneys from mice heterozygous for mutations in either BMP2, BMPR-IA or ActR-IA. Roles of BMPs 2 and 4 in mouse metanephric development in vitro were analysed by culturing whole metanephroi in the presence of BMP2, BMP4, the BMP inhibitor noggin, and BMP4 plus noggin. Ureteric branching morphogenesis and nephrogenesis were analysed. By qualitative histology, kidneys from BMP2, BMPR-IA and ActR-IA heterozygous null mutant mice were found to be the same as those from wild type mice. The kidneys of the heterozygous mice contained the normal complement of nephrons. In vitro, high concentrations of BMP4 inhibited branching of the ureteric epithelium and changed its morphology, while nephrogenesis was inhibited by 50%. A range of concentrations of BMP2 did not alter ureteric or mesenchyme morphology, or the number of glomeruli formed. Noggin did not alter metanephric development in vitro, but did block the effect of BMP4. The experiments described in this study have shown that BMP4 has distinct roles from BMP2 in metanephric development.