Indiana University-Purdue University Indianapolis (IUPUI) / Cell shape changes and signaling pathways are essential for the development and function
of the lens. During lens development proliferating epithelial cells will migrate down to the
equator of the lens, differentiate into lens fiber cells, and begin to elongate along the lens
capsule. The Fibroblast Growth Factor (FGF) signaling pathway has been extensively
studied for its role in lens fiber cell differentiation and elongation. However, the main
mediators of FGF stimulated lens fiber cell elongation have not been identified. Adaptor
proteins Crk and CrkL are SH2- and SH3-containing proteins that transduce signals from
upstream tyrosine phosphorylated proteins to downstream effectors, including Ras, Rac1
and Rap1, which are important for cell proliferation, adhesion and migration. Underlying
their diverse function, these two adaptor proteins have been implicated in receptor tyrosine
kinase signaling, focal adhesion assembly, and cell shape. To explore the role of Crk and
CrkL in FGF signaling-dependent lens development and fiber elongation, we employed
Cre/LoxP system to generate a lens specific knockout of Crk/CrkL. This led to extracellular
matrix defects, disorganization of the lens fiber cells, and a defect in lens fiber cell
elongation. Deletion of Crk and CrkL in the lens also mitigated the gain-of-function
phenotype caused by overexpression of FGF3, indicating an epistatic relationship between
Crk/CrkL and FGF signaling during lens fiber cell elongation. Further studies, revealed
that the activity of Crk and CrkL in FGF signaling is controlled by the phosphatase Shp2
and the defect observed in lens fiber cell elongation can be rescued by constitutive
activation of the GTPases Ras and Rac1 in the Crk and CrkL mutant lens. Interestingly,
the deletion of the GTPases Rap1 in the lens showed no obvious phenotype pertaining to lens fiber cell elongation. These findings suggest that Crk and CrkL play an important role
in integrating FGF signaling and mediating lens fiber cell elongation during lens
development.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/11645 |
| Date | 04 May 2016 |
| Creators | Collins, Tamica N. |
| Contributors | Zhang, Xin |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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