Spred proteins are inhibitors of the mitogen-activated protein kinase (MAPK) pathway. To investigate the physiological impact of Spred proteins in vivo, we generated mice with a trapped spred2 gene, leading to a spred2 knock-out. resulted in at least two phenotypes: first, in a proportional dwarfism and, second, in kidney failure. Spred-2-/- mice showed reduced growth and body weight (males 18g vs. 23g, 60dpn, p<0.01; n=10), a shorter tibia length (16.1 vs. 18.1mm in adult mice, p<0.01; n=26) and narrower growth plates (493±80 vs. 599±41mm at 7dpn). We detected Spred-2 expression in chondrocytes, suggesting an important function of Spred-2 in chondrocyte differentiation and bone development. Stimulation of chondrocytes with fibroblast growth factor showed elevated ERK phosphorylation in Spred-2-/- chondrocytes, which is in line with published functions of FGF receptor 3-mediated signalling in bone growth.

Furthermore, we observed that Spred-2-/- mice showed pruritus, chronic pyelitis, kidney cysts and massive lymphocytic infiltration and destruction of tubular cells. In vivo spred2 promoter studies and immunohistological stainings demonstrated Spred-2 expression in the tubular system of the kidney, in the ureter and in the epithelium of the bladder. Although the exact molecular mechanisms leading from the lack of Spred-2 expression to the severe effects in these mice are still under investigation, it becomes clear that Spred-2 plays a prominent role in the regulation of MAPK signalling.