Research outline - Lens Research Laboratory
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The lens transmits and focuses light onto the retina. To do this it needs to be transparent and to have appropriate refractive properties. This depends on the development and maintenance of a highly ordered cellular architecture. The lens consists of two forms of cells encapsulated within a basement membrane; (i) elongated fibre cells, grow to several millimetres in length, and are precisely aligned to form a regularly packed spheroidal mass, and (ii) cuboidal epithelial cells form a single-layered sheet that covers the anterior surface of the fibres. Whilst the fibre cells make up the bulk of the lens and mostly determine its optical properties, epithelial cells play a key role in maintaining an appropriate physiological environment within the lens. In addition, the epithelium contains the ‘stem cells’ that proliferate, migrate and differentiate into the new fibres that are progressively added to the fibre mass throughout life. We have focussed our attention on growth factors because of their importance in regulating cell fates in many diverse developmental systems. Using a unique lens epithelial explant culture system we have identified members of the FGF growth factor family as inducers of lens cell proliferation, migration & differentiation; responses that are induced in a progressive dose-dependent manner. We have proposed that an anterior-posterior gradient of FGF in the eye determines lens polarity and growth patterns and testing this hypothesis continues to be a major area of research activity in our laboratory. In addition to FGF, we are actively exploring the differential mitogenic effects of other growth factors primarily as a means of identifying which of these is important for regulating lens cell proliferation in the eye. Our more recent studies have also identified molecules, including members of the Wnt and Frizzled gene families, as well as putative growth factor antagonists, that appear to be essential for maintenance of the lens epithelium, primarily serving to tightly regulate its structural and functional characteristics.
In addition to better understanding normal lens developmental biology, our growth factor studies have also helped us to gain insights into the molecular basis of the major lens pathology, cataract. We have shown that members of the transforming growth factor beta (TGFß) family induce aberrant growth and differentiation of lens cells. This progressively leads to disruption of normal cellular architecture and opacification of the lens. Cataract is the most common cause of blindness in the world today. Although surgery is generally effective, in many countries it cannot keep pace with the growing demand. Moreover, complications such as aberrant growth and differentiation of lens cells left behind after cataract surgery (most commonly referred to as posterior capsule opacification), require further treatment and add to the cost of cataract management.
Because of its clinical significance it is vital to understand how TGFß induces cataractous effects on the lens and most importantly how it is regulated in the eye. This information is fundamental to understanding the molecular basis of cataract and devising strategies for prevention.
NEI/NIH grant. Lens differentiation and cataract: role for Wnt/PCP signaling. McAvoy JW and Lovicu FJ (USD$420,000; AUD$615,000)
NHMRC (National Health and Medical Research Council, Australia) McAvoy JW and Lovicu FJ. Role of primary cilia and PCP proteins in lens development: implications for lens regeneration after cataract surgery. ($399,462)
Lovicu FJ, and McAvoy, JW. 2001. FGF-induced lens cell proliferation and differentiation is dependent on MAPK (ERK1/2) signalling. Development. 128. 5075-5084.
Stump RJW, Ang S, Chen Y, von Bahr T, Lovicu FJ, Pinson K, de Iongh RU, Yamaguchi TP, Sasoon DA, McAvoy JW. 2003. A role for Wnt/ß-catenin signalling in lens epithelial differentiation. Dev. Biol. 259:48-61.
Lovicu FJ and Robinson ML (editors). 2004. “Development of the Ocular Lens”. Cambridge University Press. New York.
Lovicu FJ, Steven P, Saika S,. McAvoy JW. 2004. Aberrant lens fiber differentiation contributes to anterior subcapsular cataract formation in vivo: a process dependent on reduced levels of Pax6. Invest. Ophthal. Vis. Sci. 45:1946-1953.
Lovicu FJ, McAvoy JW. 2005. Growth Factor Regulation Of Lens Development. Dev. Biol. 280:1-14.
Iyengar L, Patkunanathan B, Lynch OT, McAvoy JW, Rasko JEJ, Lovicu FJ. 2006. Aqueous humour- and growth factor-induced lens cell proliferation is dependent on MAPK/ERK1/2 and Akt/PI3-K signalling. Exp. Eye Res. 83:667-78.
Chen Y, Stump RJW, Lovicu FJ, McAvoy JW. 2006. A role for Wnt/Planar Cell Polarity signaling during lens fiber cell differentiation? Semin Cell Dev Biol. 17:712-25.
Boros J, Newitt P, Wang Q, McAvoy JW, Lovicu FJ. 2006. Sef and Sprouty expression in the developing ocular lens: implications for regulating lens cell proliferation and differentiation. Semin Cell Dev Biol. 17:741-52.
Iyengar L, Wang Q, Rasko JEJ, McAvoy JW, Lovicu FJ. 2007. The duration of MAPK/ERK1/2 phosphorylation induced by FGF or ocular media determines lens cell fate. Differentiation. 75:662-668.
Chen Y, Stump RJW, Lovicu FJ, Shimono A, McAvoy JW. 2008. Wnt signaling is required for organization of the lens fiber cell cytoskeleton and development of lens three-dimensional architecture. Developmental Biology. 324:161-176.
Wang Q, Stump R, McAvoy JW, Lovicu FJ. 2009. MAPK/ERK1/2 and PI3-kinase signalling pathways are required for vitreous-induced lens fibre cell differentiation. Exp Eye Res. 88: 293-306.
Iyengar L, Patkunanathan B, McAvoy JW, Lovicu FJ. 2009. Growth factors involved in aqueous humour-induced lens cell proliferation. Growth Factors. 27:50-62.
Sugiyama Y, Stump RJ, Nguyen A, Wen L, Chen Y, Wang Y, Murdoch JN, Lovicu FJ, McAvoy JW. 2010. Secreted frizzled-related protein disrupts PCP in eye lens fiber cells that have polarised primary cilia.
Dev Biol. 2010;338:193-201.
Newitt P, Boros J, Madakashira BP, Robinson ML, Reneker LW, McAvoy JW, Lovicu FJ. 2010. Sef is a negative regulator of fiber cell differentiation in the ocular lens. Differentiation. 2010;80:53-67.
Wang Q, McAvoy JW, Lovicu FJ. 2010. Growth factor signaling in vitreous humor-induced lens fiber differentiation. Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3599-610.
Lovicu FJ, McAvoy JW, de Iongh RU. 2011. Understanding the role of growth factors in embryonic development: insights from the lens.
Phil Trans R Soc B. 2011; in press.