Ablation of Csk in neural crest lineages causes corneal anomaly by deregulating collagen fibril organization and cell motility |
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Authors: | Takatsuka Atsuko Yagi Reiko Koike Masato Oneyama Chitose Nada Shigeyuki Schmedt Christian Uchiyama Yasuo Okada Masato |
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Affiliation: | a Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan b Department of Cell Biology and Neurosciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan c Genomics Institute of the Novartis Research Foundation, San Diego, USA |
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Abstract: | Src family kinases (SFKs) have been implicated in the regulation of cell motility. To verify their in vivo roles during development, we generated mutant mice in which Csk, a negative regulator of SFKs, was inactivated in neural crest lineages using the Protein zero promoter in a Cre-loxP system. Inactivation of Csk caused deformities in various tissues of neural crest origins, including facial dysplasia and corneal opacity. In the cornea, the stromal collagen fibril was disorganized and there was an overproduction of collagen 1a1 and several metalloproteases. The corneal endothelium failed to overlie the central region of the eye and the peripheral endothelium displayed a disorganized cytoskeleton. Corneal mesenchymal cells cultured from mutant mice showed attenuated cell motility. In these cells, p130 Crk-associated substrate (Cas) was hyperphosphorylated and markedly downregulated. The expression of a dominant negative Cas (CasΔSD) could suppress the cell motility defects. Fluorescence resonance energy transfer analysis revealed that activation of Rac1 and Cdc42 was depolarized in Csk-inactivated cells, which was restored by the expression of either Csk or CasΔSD. These results demonstrate that the SFKs/Csk circuit plays crucial roles in corneal development by controlling stromal organization and by ensuring cell motility via the Cas-Rac/Cdc42 pathways. |
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Keywords: | Cell motility Src family kinases Csk Cre-loxP Protein zero Cornea Cas Rac1 Cdc42 Cell polarity |
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