Abstract
Specific cell shapes are fundamental to the organization and function of multicellular organisms. Fibroblast Growth Factor (FGF) signaling induces the elongation of lens fiber cells during vertebrate lens development. Nonetheless, exactly how this extracellular FGF signal is transmitted to the cytoskeletal network has previously not been determined. Here, we show that the Crk family of adaptor proteins, Crk and Crkl, are required for mouse lens morphogenesis but not differentiation. Genetic ablation and epistasis experiments demonstrated that Crk and Crkl play overlapping roles downstream of FGF signaling in order to regulate lens fiber cell elongation. Upon FGF stimulation, Crk proteins were found to interact with Frs2, Shp2 and Grb2. The loss of Crk proteins was partially compensated for by the activation of Ras and Rac signaling. These results reveal that Crk proteins are important partners of the Frs2/Shp2/Grb2 complex in mediating FGF signaling, specifically promoting cell shape changes.
Highlights
During the development of complex multicellular organisms, changes in epithelial cell morphology are essential for the tissue-specific cell differentiation patterning that leads to the subsequent formation of functional organs (Settleman and Baum, 2008)
These three lines of evidence established that Crk proteins are essential mediators of Fibroblast Growth Factor (FGF) signaling whose specific function relates to the fiber cell elongation that occurs during lens development
Since our biochemical and genetic data did not support a functional role for the direct interaction between FGF receptors and the Crk protein, we explored whether FGF signaling may engage Crk indirectly through intermediaries
Summary
During the development of complex multicellular organisms, changes in epithelial cell morphology are essential for the tissue-specific cell differentiation patterning that leads to the subsequent formation of functional organs (Settleman and Baum, 2008). The experiments revealed two related proteins called Crk and Crkl that linked the FGF pathway with another signaling system When these two proteins were removed from the lens cells, the lens cells were still able to specialize, but could no longer grow in length. Crk/Crkl deficient animals phenocopied Rac but not Rap mutants, and activation of Rac and Ras signaling partially reversed the observed lens elongation defects caused by the deletion of Crk and Crkl These results show that the Crk family of adaptor proteins are essential partners of the Frs2/Shp2/Grb complex that forms during FGF signaling, and are required for stimulating the actin reorganization that is necessary for the morphological shaping of lens cells
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