The Thomas Linsenmayer Lab
Our laboratory studies a number of aspects of the developmental biology of the cornea. The animal model we use is the embryonic chicken, as the cornea of this species has a number of features that make it advantageous for developmental studies. For example, the cornea forms in a series of discrete stages that for experimentation can be cleanly separated from one another. In addition, the embryonic chick cornea is essentially indistinguishable from the human cornea both in its structure and molecular composition. The two areas we are currently investigating are the developmental innervation of the cornea and a novel mechanism we have discovered in corneal epithelial (CE) cells that protects their DNA from damage by UV light and other sources of reactive oxygen species (ROS). More details about each area are given below.
The cornea is one of the most densely innervated tissues in the body. Corneal nerves, which originate from the ophthalmic branch of the trigeminal ganglion, are largely sensory (Figure 1). In the adult they respond to noxious stimuli by transducing these as sensations of pain, which protect the cornea from damage by modulating the blinking reaction and increasing the production of tears. Nerves also maintain the cornea in a healthy state through the production of “trophic” factors, such as Substance P. However, all of these functions can be lost, either temporarily or permanently, following damage to that can result from infections, mechanical injury, or following certain surgical procedures such as laser visual correction. Despite its importance, little is known concerning the mechanisms involved in corneal innervation. To address these issues, we have been studying a number of aspects of corneal innervation including the signaling cues that are responsible for regulating each stage of corneal innervation and the interaction between the corneal nerves and specialized CE cells that result in the formation of novel nerve endings.
Figure 1. Corneal nerves (red) growing around the cornea (center) forming a peri-corneal ring at embryonic day 7.
Protection of Corneal Epithelial Cell DNA from UV Damage
UV light constitutes a major environmental insult to all exposed tissues of the body, including those comprising the cornea. UV light can damage a wide variety of macromolecular components including DNA. This damage can be direct, or it can be indirect through the generation of ROS. CE cells, however, seem to be refractory to such damage. Primary cancers of these cells are extraordinarily rare, even though this tissue is transparent and constantly exposed to ROS-generating UV light and O2. This suggests that CE cells have evolved defense mechanisms that prevent damage to their DNA. Our studies suggest that one of these mechanisms involves having the iron-sequestering molecule ferritin in a nuclear location as opposed to the cytoplasmic localization typical in other cell types. This localization prevents the free iron catalyzed conversion of UV-induced hydrogen peroxide and superoxide to the hydroxyl radical, which is the most active ROS. Ongoing studies involve further elucidating the mechanism through which the CE ferritin undergoes nuclear transport in a tissue-specific manner, and how this molecule protects DNA from damage.