Developmental Origins of Health and Disease: Kidney adysplasia and variable hydronephrosis, a new mutation affecting the odd-skipped related 1 gene in the mouse, causes variable defects in kidney development and hydronephrosis

mammalian kidney development is a complex process regulated by several transcription factors and regulatory proteins, including EYA1, GATA3, LHX1, RET, SIX2, PAX2, SALL1, LIM1, GDNF, WT1, and OSR1 (4). The kidney develops from mesenchymal progenitor cells in the intermediate mesoderm, from which the metanephric mesenchyme and the nephric duct both arise. By embryonic day 10.5 (E10.5), the metanephric mesenchyme stimulates the adjacent nephric duct to invade the nephric tissue, initiating reciprocal signaling interactions that direct growth and branching of the embryonic kidney. The odd-skipped related 1 (Osr1) gene, one of two mammalian orthologues of the Drosophila odd-skipped (odd) gene (18), encodes one of the earliest transcription factors expressed during kidney development and is required for metanephric mesenchyme formation (11, 22). Its expression in the intermediate mesoderm activates the formation and expansion of mesenchymal cells, initiating a cascade of other transcription factors. Deletion of Osr1 in the mouse completely blocks expression of key transcription factors in the metanephric mesenchyme, halting development of the embryonic kidney (11, 21, 22). Here, we report a new recessive mutation (kidney adysplasia and variable hydronephrosis, kavh) in the mouse that leads to downregulation of Osr1 transcript, causing variable kidney agenesis, hypoplasia, and hydronephrosis. The mutation is closely linked with a reciprocal translocation, T(12;17)4Rk (hereafter T4Rk), whose Chromosome (Chr) 12 breakpoint is upstream from Osr1. The kidney anomaly has not segregated from the translocation during inbreeding of the strain, suggesting that the translocation breakpoint on Chr 12 may disrupt a regulatory region that is needed for normal Osr1 expression. The kavh/kavh mutant provides a model for better understanding the earliest stages of kidney development and testing potential therapies for hydronephrosis.