Alpha-crystallin Gene Disruption In The Mouse

National Eye Institute

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Abstract

The alpha-crystallins comprise a large fraction of the soluble protein in the vertebrate lens where they were, for many years, believed to function solely as structural proteins. Lenticular alpha-crystallin is comprised of two similar subunits alphaA and alphaB, each encoded by a single gene. They are related to the small heat shock proteins, and in vitro they exhibit molecular chaperon activity, autokinase activity, and interact with and affect the state of several cytoskeletal components. Alpha-Crystallin, especially alphaB-crystallin, has been shown to be a normal constituent of many non-lenticular tissues, and has been detected in cytoplasmic inclusion bodies found in several human pathological conditions. Toward understanding the major roles of alpha-crystallin in vivo, we previously generated alphaA- and alphaB-crystallin gene knockout mice and alphaA-/alphaB-crystallin gene double knockout mice. A predoctoral fellow has been studying the lenses of alphaA/alphaB double knockout mice. These mice are microphthalmic and exhibit severe cataract with a disorganized fiber cell compartment characterized by a sphere of degraded cells surrounding the lens nucleus and migration of newly differentiating fiber cells anteriorly, pushing the nucleus to the posterior of the lens and eventually rupturing the lens capsule. Examination of the expression patterns of integrins and extracellular matrix proteins has not yet identified any significant differences in the distribution of these molecules. In collaboration with Joseph Horwitz (UCLA) we are reexamining the constituents of inclusion bodies in lenses of alphaA knockout mice. With the current techniques, we are discovering significant amounts of various proteins in addition to alphaB in these bodies. A collaboration with Usha Andley (Washington U.) has shown that some lens cells cultured from alphaB knockout mice hyperproliferate and undergo ploidy changes, suggesting that alphaB may be essential for maintenance of normal cell cycling and genomic stability. We are currently involved in collaborations with laboratories around the world studying the functions of alphaB in the heart, muscle, nervous system, immune system, and eye.