Gene disruption of Spred-2 causes dwarfism.
The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase ( MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/ MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2(-/-) mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2(-/-) chondrocytes in comparison to Spred-2(+/+) chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.[1]References
- Gene disruption of Spred-2 causes dwarfism. Bundschu, K., Knobeloch, K.P., Ullrich, M., Schinke, T., Amling, M., Engelhardt, C.M., Renné, T., Walter, U., Schuh, K. J. Biol. Chem. (2005) [Pubmed]
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