Cataract is the most common cause of blindness in the world today. Surgery is generally very effective in restoring sight;however, a common complication is the development of posterior capsule opacification. This is caused by aberrant growth and differentiation of lens cells that remain in the capsular bag after surgery. Our approach to circumvent this problem is to identify the conditions required for normal growth and differentiation of residual lens cells and apply this new information to promote regeneration of normal lens structure and function. Our previous NEI-funded studies showed that members of the FGF growth factor family could induce fiber differentiation in vitro and subsequent studies by our group and others have now provided compelling evidence that fiber differentiation in vivo depends on FGF signaling. This knowledge is fundamental to devising strategies for lens regeneration after cataract surgery. However, if we are to successfully regenerate transparent lenses with normal focusing abilities, in addition to being able to initiate and promote fiber differentiation, we need to be able to recapitulate the coordinated cell behavior that is required to generate the exquisite three-dimensional organization of fibers (and epithelial cells) that is the central feature of normal lens morphogenesis. In our current NEI-funded project we have identified Wnt/Frizzled signaling through the planar cell polarity (Wnt-Fz/PCP) pathway as critical for promoting the precise alignment/orientation of fibers. We have also shown that epithelial cells provide a polarizing cue that aligns/orients elongating fibers. To exploit these novel findings this renewal application aims to elucidate the mechanism(s) whereby activation of Wnt-Fz/PCP signaling translates into polarized fiber cell behavior and establishes the global alignment/orientation of fibers that is critical for normal lens morphogenesis. In section 1 of the project we will use FGF to induce fiber differentiation in our well- characterized epithelial explant system to identify the mechanism whereby components of the Wnt-Fz/PCP signaling pathway organize the lens cell cytoskeleton and promote coordinated alignment/orientation. In section 2, using epithelial explants and complementary transgenic approaches we will both promote and inhibit Wnt bioavailability and/or Wnt signaling to determine if epithelial-derived Wnt ligand provides a directional cue that draws fibers to poles This project will provide vital new information about mechanisms and molecules that are required to promote the regeneration of lens structure and function and in so doing will address key objectives identified within the Lens and Cataract Program of the NEI.
With approximately 20 million people affected, clouding of the lens (cataract) is the most common cause of blindness in the world today. Although surgery can initially be very effective in restoring sight, in the longer term complications are common and often result in the development of a secondary cataract. A central aim in our laboratory is to devise molecular strategies that (i) prevent the aberrant lens cell behavior that occurs after surgery, and (ii) promote normal patterns of lens cell growth and differentiation so that lens clarity is maintained.
|Dawes, L J; Shelley, E J; McAvoy, J W et al. (2018) A role for Hippo/YAP-signaling in FGF-induced lens epithelial cell proliferation and fibre differentiation. Exp Eye Res 169:122-133|
|Zhao, Guannan; Bailey, Charles G; Feng, Yue et al. (2018) Negative regulation of lens fiber cell differentiation by RTK antagonists Spry and Spred. Exp Eye Res 170:148-159|
|Shu, Daisy Y; Wojciechowski, Magdalena C; Lovicu, Frank J (2017) Bone Morphogenetic Protein-7 Suppresses TGF?2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention. Invest Ophthalmol Vis Sci 58:781-796|
|Wojciechowski, Magdalena C; Mahmutovic, Leila; Shu, Daisy Y et al. (2017) ERK1/2 signaling is required for the initiation but not progression of TGF?-induced lens epithelial to mesenchymal transition (EMT). Exp Eye Res 159:98-113|
|McAvoy, J W; Dawes, L J; Sugiyama, Y et al. (2017) Intrinsic and extrinsic regulatory mechanisms are required to form and maintain a lens of the correct size and shape. Exp Eye Res 156:34-40|
|Shu, Daisy Y; Lovicu, Frank J (2017) Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis. Prog Retin Eye Res 60:44-65|
|Das, Shannon J; Lovicu, Frank J; Collinson, Emma J (2016) Nox4 Plays a Role in TGF-?-Dependent Lens Epithelial to Mesenchymal Transition. Invest Ophthalmol Vis Sci 57:3665-73|
|Lovicu, F J; Shin, E H; McAvoy, J W (2016) Fibrosis in the lens. Sprouty regulation of TGF?-signaling prevents lens EMT leading to cataract. Exp Eye Res 142:92-101|
|Audette, Dylan S; Anand, Deepti; So, Tammy et al. (2016) Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression. Development 143:318-28|
|Sugiyama, Yuki; Shelley, Elizabeth J; Yoder, Bradley K et al. (2016) Non-essential role for cilia in coordinating precise alignment of lens fibres. Mech Dev 139:10-7|
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