Lens development and disorders - molecular biology and genetics

Published on May 31, 2016   41 min
0:00
Hello. My name is Rachel Gillespie. I'm a research associate at Manchester Centre for Genomic Medicine within the University of Manchester in the UK.
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Today I'm going to talk about the molecular mechanisms underlying development of the ocular lens, the physiological processes in place to establish lenticular transparency, and the genes and proteins important in each of these processes. I will also discuss the genetic basis of lens abnormalities, current approaches to the diagnosis of this group of conditions, and the utility of genetic testing in these cases.
0:38
The vertebrate eye is an incredibly complex sensory organ that detects and reacts to light to allow vision. In this, the ocular lens is crucial. As illustrated in the diagram, the lens is central to the visual process. Located within the posterior chamber of the anterior segment, just behind the cornea, iris, and trabecular meshwork of the anterior chamber, the adult lens is approximately 4 millimeters thick, 9 millimeters in diameter, and comprised of around 3,000 layers of cells. The lens developed to form a curved, flexible structure anchored by the zonules of Zinn and suspensory ligaments that are connected to the ciliary muscle of the ciliary body. The ciliary muscle contracts to make the lens more convex, and relaxes to flatten it. Via this changing of shape, the lens is able to alter this optical power to maintain clear focus on objects of varying distance in a process known as accommodation. The lens also plays an important role in the refraction of light. Whilst the majority of refraction takes place at the air-cornea interface, the lens is responsible for fine-tuning light refraction for accurate focusing onto the macula within the retina for detailed vision. To facilitate this, the lens has evolved a specialized and complex microarchitecture that absorbs a minimal amount of light visible to the human eye by preventing light scatter. This enables the establishment of an unparalleled level of transparency and a high refractive index.
2:09
The vertebrate lens has three main components, the nuclear and cortical lens fibers, the subcapsular lens epithelium, and the lens capsule. The aqueous and vitreous humors bathe the anterior and posterior surfaces respectively, supplying nutrients, ions, and water by diffusion across the semipermeable membrane of the lens capsule. Lens fiber cells are the principal component of the structure, accounting for 95% of the total lens volume. The elaborate arrangement that lens fibers form facilitates transparency and light transmission, whilst the intricate morphology of individual fiber cells is important for tissue integrity, stress resistance, and lens metabolism. The schematic diagram shows the cellular organization of the lens. The Primary Fibers, PF, formed early in development, are concentrated at center of the structure, within the fetal nucleus. Elongated secondary fiber cells surround the nucleus and fill the lens mass. Young secondary fibers, originating from a stem-cell-like niche of cells near the lens equator, migrate towards the center of the lens and eventually undergo terminal differentiation, during which they degrade their entire organelle contents. This arrangement means organelle free cells are concentrated at the center of the lens in the Organelle-Free Zone, or OFZ, in the diagram. An epithelial layer, EPI, surrounds the lens fibers on the anterior surface, and the entire structure is enclosed in the lens capsule. Figures b and c are scanning electron and light microscopy images of a cross-section through fiber cells of the red lens from an excellent review by Steve Bassnett. They shown in beautiful detail the hexagonal shape and higher-order arrangement that lens fibers take on to facilitate the transparency of the lens. And Images e and f show fiber cell protrusions of cells deep within the lens mass known as microplicae. It is thought that these protrusions are integral for securing immediately adjacent cells together so as to prevent tissue damage, lens deformation, and fiber disorganization during accommodation and biological stress conditions.
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In early embryogenesis, the prospective lens is specified in a field of cells within the non-neural ectoderm of the anterior neural plate border following neural plate formation. At around 28 days gestation in humans, the lens placode forms as these cells divide and elongate in response to the closely-opposed lens vesicle. Cells of the pre-placodal ectoderm elongate, becoming more cuboidal and increasing in number, causing a defined region to thicken without affecting the surrounding ectoderm, forming the lens placode. At approximately 29 days gestation, the optic vesicle and lens placode invaginate. The lens placode eventually pinches off from the surface ectoderm to form an almost focal but hollow vesicle. The lens vesicle is usually formed by day 36 of human gestation. Polarity is established within the lens vesicle when cells on the posterior side of the sphere, that is the side closest to the developing neural retina, elongate to the anterior surface. These cells are the primary lens fibers and will continue to become concentrated at the center of the lens in a region known as the fetal nucleus. Meanwhile, cells on the anterior wall differentiate into an epithelial layer known as the anterior lens epithelium. Subsequently, cells within the stem-cell-like niche just above the equatorial margin begin to proliferate, migrate posteriorally, and align line just below the lens equator. There, they extend posteriorally until their tips abut at the sutures, encircling the primary fibers and differentiating into secondary lens fibers. This process results in a substantial increase in lens size and mass. Secondary fibers are continually added to the lens throughout life, although at a reducing rate with increasing age. Terminal differentiation of secondary fiber cells results in degradation of all cellular organelles, including the nucleus. Accordingly, in the absence of cell turnover, each fiber cell has a lifelong role within the lenticular mass. Lens fibers form a highly organized, radially layer, and tightly packaged arrangement that is critical for transparency of the lens.
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Lens development and disorders - molecular biology and genetics

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