Hypoxia Regulation of the Lens

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Project Summary/Abstract This application seeks to identify novel mechanisms and regulatory pathways required to achieve the structure and function of the eye lens. The lens consists of a surface layer of epithelial cells that during embryogenesis, and throughout life, differentiate into lens fiber cells that make up the core and bulk of the lens. To achieve their mature structure and transparent function, newly-formed lens fiber cells must complete a sequential program of cellular remodeling hallmarked by the complete elimination of cellular organelles and the tightly controlled expression of specialized lens proteins. Disruption of the lens fiber cell remodeling program causes defective lens structure and cataract formation so that identification of these mechanisms and regulatory pathways is critical for advancing our understanding of mature lens formation and pathology. We have recently discovered that a key regulator of mitochondrial degradation in erythrocytes, called BNIP3L, is required for the specific elimination of mitochondria, endoplasmic reticulum and Golgi apparatus in the embryonic lens during formation of the lens organelle-free zone. These studies identify the first requirement for the elimination of non- nuclear organelles during the remodeling of embryonic lens fiber cells and they establish an entirely novel function for BNIP3L in the degradation of endoplasmic reticulum and Golgi apparatus. Experiments proposed in AIM1 now seek to advance these findings by establishing a novel requirement for BNIP3L in the elimination of these organelles during the remodeling of adult lens fiber cells and they seek to reveal the mechanisms, regulatory pathways and auxiliary proteins required for their BNIP3L-dependent elimination. Lacking a blood supply the lens contains a diminishing oxygen gradient from the lens surface to the lens core. Experiments AIM 2 are designed to test the novel hypothesis that lens hypoxia is a novel requirement for lens structure and transparency through the hypoxia-dependent control of organelle-elimination in lens fiber cells and the regulation of critical genes including BNIP3L, the cell-cycle exit protein p27 and the structural protein CP49, through activation of the master regulator of the hypoxic response, hypoxia-inducible transcription factor HIF1a. The successful completion of these AIMs will have a significant long-term impact on our understanding of the cellular remodeling pathways leading the mature structure and transparent function of the eye lens. The results are also expected to advance the identification of cellular remodeling pathways required for the formation and function of more complex tissues.