Cataract disease represents an important health problem that accounts for 22% of all cases of blindness. Over 2 million cataract operations are performed in the US annually. The etiology of cataract disease remains unclear but is clearly multifactorial. Ther heritable predisposition to cataract disease suggest that genetic factors can contribute to the pathogenesis of cataracts. Congenital cataracts whcih manifest as a central (nuclear) opacifications are believed to represent perturbations in normal lens cell differentiation; however, molecular mechanisms governing cataract formation and normal lens differentiation are poorly understood. Myc-family genes (c- N- and L-myc) are believes to play key regulatory roles in normal cell growth and differentiation. Each gene is differentially expressed throughout mammalian development with dramatic changes in the expression of specific myc members coinciding with key developmental transitions in many cell lineages. We ahve demonstrated that as lens fiber cells progress through their developmental program myc-family genes are differentially regulated with respect to developmental stage. For instance, proliferating undifferentiated lens cells express c-myc and L-myc. As these immature cells undergo proliferative arrest and initiate differentiation, both c-myc and L-myc are down-regulated. In contrast, N-myc transcripts are not detectable in immature cells but become abundant at the onset of differentiation. The goal of these studies is to determine the physiological significance of myc in lens differentiation and in the development of cataract disease. To achieve these objectives, we will produce transgenic mice that aberrantly express myc-family genes in the developing lens. With the alphaA-crystallin promoter-enhancer element, we have demonstrated that forced expression of the L-myc gene in differentiating lens cells induces large nuclear congenital cataracts in all cases. Nuclear congenital cataracts may be related to defected lens development and suggests that myc serevs an important role in normal lens cell differentiation. The focus of the proposed studies are (1) to characterize further the structural and molecular features of these alphaA crystallin promoter-driven L-myc transgenic mice, (2) to generate and characterize similar transgenic animals with the c-myc gene, and (3) to utilize dominant interference to abrogate N-myc activity in actively differentiating lens fiber cells, (4) to explore the xpression and function of myc family homologues in the lens of Xenopus laevis.
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