Lens cell proliferation, differentiation and survival are tightly regulated to achieve the normal developmental pattern and structure of the lens. Growth factors are likely the key regulators of these cellular events, but very little is known about the growth factor signaling pathways in the lens. Ras is a small GTP-binding protein downstream of growth factor receptor tyrosine kinases (RTKs) and plays a critical role in growth factor signaling. In the last grant period, we demonstrated that Ras is required for cell proliferation but not for the initiation of fiber cell differentiation during normal lens development. Other investigators have shown that signals activated by fibroblast growth factor receptors (FGFRs) are essential for fiber cell differentiation and lens cell survival. In this grant application, we will continue our investigation of the RTK-Ras signaling pathway in the lens.
In Specific Aim 1 and 2, experiments are proposed to determine the role of Sprouty and ERK in lens development. Sprouty is a negative regulator of the RTK-Ras pathway and ERK is a downstream effector of Ras.
In Specific Aim 3, we will explore the cell death mechanisms induced by FGFR signaling deficiency in mouse lens. The proposed experiments will provide further insights into potential ways to block lens cell proliferation and eliminate aberrant cells in the lens. Such knowledge is important for the development of methods to prevent and treat posterior capsular opacification (PCO), the most common complication of cataract surgery. Moreover, the results of this work will expand our understanding of growth factor signaling in cell proliferation and cell survival in other developmental systems and disease processes such as cancer. The purpose of this study is to investigate growth factor signaling in the developing mouse lens. This knowledge will help to develop new methods to prevent and treat posterior capsular opacification (PCO), the most common complication of cataract surgery.
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|Zhang, Jinglin; Upadhya, Dinesh; Lu, Lin et al. (2015) Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development. PLoS One 10:e0117089|
|Upadhya, Dinesh; Ogata, Masato; Reneker, Lixing W (2013) MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development. Development 140:1573-82|
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|Newitt, Peter; Boros, Jessica; Madakashira, Bhavani P et al. (2010) Sef is a negative regulator of fiber cell differentiation in the ocular lens. Differentiation 80:53-67|
|Reneker, Lixing W; Bloch, Amy; Xie, Leike et al. (2010) Induction of corneal myofibroblasts by lens-derived transforming growth factor beta1 (TGFbeta1): a transgenic mouse model. Brain Res Bull 81:287-96|
|Maddala, Rupalatha; Reneker, Lixing W; Pendurthi, Bhavana et al. (2008) Rho GDP dissociation inhibitor-mediated disruption of Rho GTPase activity impairs lens fiber cell migration, elongation and survival. Dev Biol 315:217-31|
|Xie, Leike; Chen, Huiyi; Overbeek, Paul A et al. (2007) Elevated insulin signaling disrupts the growth and differentiation pattern of the mouse lens. Mol Vis 13:397-407|
|Fan, Xingjun; Reneker, Lixing W; Obrenovich, Mark E et al. (2006) Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model. Proc Natl Acad Sci U S A 103:16912-7|
|Xie, Leike; Overbeek, Paul A; Reneker, Lixing W (2006) Ras signaling is essential for lens cell proliferation and lens growth during development. Dev Biol 298:403-14|
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