Lipid dismantling of lens organelles for clear vision.

Abstract

the cornea, lens and retina. The lens is a bi convex, transparent structure that functions like a camera lens, allowing the passage of light and focusing it on the retina. Cataracts are the result of changes in lens transparency that impede the passage of light, and they account for almost 50% of the total cases of blindness in adults aged 50 years and over. Identifying the mechanisms underlying lens transparency might thus improve our understanding of cataract biology. Writing in Nature, Morishita et al. provide crucial, long-sought information about how lens transparency is achieved during normal development. Thanks to its high refractive index, the lens can easily bend light to focus it on the retina — a consequence of the tight packing of structural proteins in the lens called crystallins. Crystallins comprise up to 60% of the total mass of the mature lens, a much higher protein-concentration level than that of any other tissue. The lens contains a type of epithelial cell that has evolved to undergo a unique process of differentiation that enables the cells to become transparent and to minimize light scattering. To achieve transparency, intracellular organelles are degraded during development to produce what is termed the organelle-free zone of the lens. Retention of organelles compromises lens transparency, and results in the formation of cataracts. An intracellular degradation pathway called autophagy — the only previously known pathway for eliminating whole organelles — was initially thought to contribute to the formation of the organelle-free zone. However, researchers subsequently found that organelle degradation still occurs during lens differentiation in autophagy-deficient mice. Now, the same research group describes a previously unknown, two-step mechanism by which organelles are cleared in lens cells (Fig. 1). The group finds that this mechanism is evolutionarily conserved in both zebrafish and mice. The first step consists of the formation of small pores that permeabilize the lipid membranes of organelles. This serves as a trigger for the second step: recruitment of an enzyme that degrades the organelles’ lipid membranes. Morishita and colleagues took a micro scopybased approach to monitor the degradation of fluorescently tagged organelles in the zebrafish lens. They identified genes expressed at high levels in the lens, and used a gene-editing method to block the expression of these genes and then assessed the effect. This revealed that the gene hrasls is required for organelle degradation during lens differentiation. The gene encodes a phospholipase enzyme, which is a member of the HRASLS (also known as PLAAT) family of proteins. These enzymes catalyse the breakdown of phospholipids — the main structural component of cellular membranes. Crucially, Morishita et al. report that, in zebrafish deficient in hrasls, and in mice deficient in the equivalent gene, Hrasls3, organelles are retained during lens differentiation. This results in defects in lens transparency, alterations in the light-refractive functions of the lens, and cataracts. The authors show that the targeting of HRASLS in zebrafish to organelles depends on a particular region of the protein — the carboxy-terminal transmembrane domain. HRASLS is located in the cytosol in the early stages of cellular differentiation, and then relocates to organelles, including mitochondria, the nucleus, lysosomes and the endoplasmic reticulum, immediately before their degradation. This work is the first to demonstrate the dismantling of entire Developmental biology