Normal lens development and differentiation is controlled by programmed responses to growth factors. Macrophage migration inhibitory factor (MIF) is a delayed early response factor expressed with developmental control in the lens. We have defined the minimal promoter of human MIF and are defining mechanisms responsible for induction by growth factors (FGF) and proto-oncogenes (c-myc). MIF belongs to a family of small isomerases and exhibits D-dopachrome tautomerase activity. We have cloned and mapped MIF and a related gene. Candidate targets for MIF function are pRb (retinoblastoma protein) and p130. With aging, levels of MIF mRNA decline in all tissues except neural tissue. We have also characterized a fatty-acid binding protein, LP2, which is developmentally regulated in lens. Molecular modelling suggests that LP2 might be susceptible to oxidation in cataract. The properties of the lens also depend on its molecular constituents, particularly the crystallins. In work on mammalian crystallins, we have shown that eta-crystallin is an ALDH1, an enzyme of retinoic acid synthesis overexpressed in lens. In the species in which it has been recruited, eta-crystallin is also the major form of ALDH1 in retina, iris, and cornea. We find that lens-specific expressions of another recruited crystallin, zeta-crystallin, depends on Pax-6 but is fine-tuned by a consensus MARE (maf response element) and a consensus Sox site occupied in brain but not lens. Tissue specificity in Pax-6 effects may also arise through different patterns of alternative splicing in different eye tissues, resulting in different DNA-binding activities. A highly conserved intronic sequence discovered in bovine and Xenopus genes for Pax-6 is implicated in this process. We have also cloned the promoter of human mu-crystallin, a novel enzyme that shows preferred expression in photoreceptors. Molecular modelling has been used to investigate the structure of AIM1, a melanoma-associated protein related to beta-gamma-crystallin, which has been discovered by colleagues at NCHGR. A common role for proteins of this superfamily in control of cytoskeletal structure is proposed.
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