Guest Blogger Danio:
In my introductory post I mentioned that my research focuses on the genetics of hereditary deaf-blindness, specifically Usher syndrome. As it’s likely that many of you have never heard of it, I thought I’d kick it up a notch with some sciency posts on what we know about Usher syndrome and what we think we can contribute to the diagnosis and treatment of the disease.
Usher syndrome is a genetically recessive condition characterized by hearing impairment, usually from birth, which is due to the degeneration of sensory neurons in the inner ear, and blindness due to retinal degeneration, which begins to occur in childhood or adolescence and progresses through several decades. Additionally, some Usher patients have balance problems associated with the sensory cell loss in the ear. There is a great deal of variation in the clinical presentation of the disease, and three clinical subtypes can be classified by the severity and age of onset of the symptoms. Usher syndrome affects about 1 in 17,000 Americans, and there are a number of populations around the world where the incidence is higher due to founder effects or intermarriage.
To begin to understand the pathology of this disease, one needs to focus on the affected cell types: mechanosensory hair cells and photoreceptors. Both are highly specialized types of sensory cells, but they’re performing essentially the same function, namely receiving an environmental stimulus and converting it into an electrical signal that is transmitted to the brain for interpretation. Although the nature of the stimuli–sound and light–are quite different, they are processed in much the same way, and thus it is not surprising to find a number of structural and functional similarities between photoreceptors and hair cells.
Schematic representation of the sensory cells in the eye and the ear affected by USH. (A) Scheme of a rod photoreceptor cell. The apical extensions of cells of the retinal pigment epithelium (RPE) evolve the tips of light-sensitive outer segments (OS) of photoreceptor cells. The OS are linked via a connecting cilium (CC) to an inner segment (IS). Calycal processes (CP) ensheath the proximal outer segment. Nuclei (N) of photoreceptor cells are localized in the outer nuclear layer (ONL). Synaptic terminals (S) link photoreceptor cells and 2nd-order neurons, bipolar and horizontal cells. (B) Scheme of a mechanosensitive hair cell. The apical part of hair cells carries numerous rigid microvilli-like structures, improperly named stereocilia (SC, arrows), where the mechanotransduction takes place. They are anchored in the actin filament-rich cuticular plate (CP). Lateral to the longest stereocilum a kinocilium (black arrowhead) is present. Its basal body is localized in the pericuticular region (gray arrowheads). N, nucleus; S, synaptic junctions between hair cells and efferent and afferent neurons. From Reiners, et al. 2006 Experimental Eye Research volume 83
Sensory neurons are constantly stimulated with a complex array of information. Retinal cells respond to all wavelengths of light within the visible spectrum as well as transmitting information about total light levels and movement. Mechanosensory hair cells can not only respond to physical contact by sound waves, they transmit information detailed enough to determine whether the sound waves in question were generated by a lover’s whisper, breaking glass, or a bow being drawn across the strings of a cello. Selective pressures on the importance of meeting the high-throughput demands of intercepting and conveying such complex stimuli have driven the evolution of specialized structures in these cells. On the receiving end are intricately organized membranes built to respond to the environmental signals. In photoreceptors, the outer segment consists of stacked disc-shaped membranes into which light-sensitive visual pigment molecules called opsins are embedded. In the hair cell, the sterocilia (which are not true cilia, but actin bundles projecting into the environment) move when they encounter sound waves, opening channels through which ions can enter the cell and trigger a response.
On the outbound side of things, these sensory neurons have evolved a mechanism by which they can adequately relay the nuances of the environmental input they have received. The constant bombardment of information these cells endure is something along the lines of the chaos of the trading floor of the NYSE, 24/7. A conventional neuron relying on action potentials to fire would be woefully overmatched in such a situation. Instead, photoreceptors and hair cells keep stockpiles of neurotransmitters tethered to the cell membrane. When the cell is stimulated by the environmental signal, these neurotransmitters are released into the synapse, imparting a graded, refined message to the waiting second order neurons.
The presence of a true cilium is another commonality between these cells, although its function in each is quite distinct. The comparative subcellular structure and function of hair cells and photoreceptors strongly suggests that they were derived from a common cellular ancestor. If, based on this, you suspect that the molecular regulation of sensory cell function is also conserved, you’d be absolutely right. In Part II, I’ll introduce the proteins affected in Usher syndrome and describe what they tell us about the pathology of the disease.