Pharyngula

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.

i-5e689a0eb8c0e0e81469983afb558096-reinersEER06fig.jpg
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.

Comments

  1. #1 Gregory Kusnick
    August 13, 2008

    …there are a number of populations around the world where the incidence is higher due to founder effects or intermarriage.

    This is the deaf Cajuns with tunnel vision, who sign really small? There was a PBS documentary about them a few years ago.

  2. #2 Bacopa
    August 13, 2008

    Makes sense when you consider the lateral line organs of fish give them very accurate spatial information, just like their vision. Some fish also have electric organs that give them spatial information and I wonder whether there’s an electric fish version of Usher syndrome that affects electric organs as well as lateral line sense and vision.

    BTW, I breed both White Clouds (T. albonubes) and cherry barbs (B. titteya), close kin to Danios. All this happens in a 75gal choked with Crypts, Bacopa, and staghorn algae. Obviously for all the Bacopa I have to have tons of light. Two apartment kitchens worth of light go right into the tank. Filtration is a powerhead sponge and a fry friendly Hamburg mat type setup. I do not vacuum substrate. I can’t get to it. I dripline five gallons of water out five days a week.

    I have several crops of cherry barbs in the summer . I don’t use my central heat and I don’t heat the tank. Once the tank temps drop below 78 the White Clouds perk up, and if the tank temps get below 72. they breed like crazy.

  3. #3 Danio
    August 13, 2008

    This is the deaf Cajuns with tunnel vision, who sign really small? There was a PBS documentary about them a few years ago.

    Yes, members of Acadian population of Nawlins have Usher syndrome (type 1c, specifically–more on that later :). Good catch.

  4. #4 Helioprogenus
    August 13, 2008

    I believe Neil Shubin covered a segment of this in his book “Your Inner fish”. Do these sensory cells also share the same Hox genes? I know their origins in embryonic development are different from each other, yet their development and rate of expression must be dependent on Hox genes. Perhaps it’s the same regulatory genes that function to generate these two sensory cells. It could also explain other symptoms that present themselves with Usher syndrom.

  5. #5 Skepcanuck
    August 13, 2008

    Hi Danio-

    Thanks for the article — it’s timely and relevant to me, and I look forward to reading the next part(s). I’m interested in finding out more about Usher research in general. My son has Usher syndrome, and though he is amazingly successful with his cochlear implants, we still have many challenges ahead of us.

    We support research through the Foundation Fighting Blindness — do you think they are the most effective channel for our time and money?

  6. #6 clamboy
    August 13, 2008

    I hope you will provide some context for the “Cajun deaf…who sign really small” characterization. Historical details would help, as well as the story of Danny DelCambre, among others.

    Also, a primer on the thriving Deaf-Blind community of Seattle would round out the narrative of pathology. Maybe you could talk about DBSC? WSDBC? Seabeck? The Lighthouse?

  7. #7 Stefan
    August 13, 2008

    Interesting post. What, if anything, does this syndrome and your research tell us about how our sensory organs evolved? Just curious.
    Thanks.

  8. #8 Nobody
    August 13, 2008

    Nice to see some SCIENCE blogging occurring in here for a change. Keep up the good work!!!

  9. #9 Bobber
    August 13, 2008

    Back in my younger days, I dated a young woman who was deaf and who also suffered from Usher’s Syndrome. I recall going to movies with her and signing in her hand – we saw Batman at the theater and I didn’t remember a single bit of the plot, everything was going from my ears through my hands.

    She had a lot of problems with her sense of balance, and while she informed me that it was due to the Usher’s, she couldn’t adequatly explain why. After all these years, it is fascinating to me to read about the science behind it.

    Thank you for this post, and for reminding me of those younger days.

    (P.S. – I used to interpret at the meetings of the Deaf/Blind Association of Connecticut. The leader of the group at the time told the nastiest, filthiest dirty jokes I’d ever “heard”. Boy, but jokes in sign language are just so… graphic!)

  10. #10 Nerd of Redhead
    August 13, 2008

    Can’t wait to read part 2.

  11. #11 Danio
    August 13, 2008

    Bacopa @2: Interesting question. The electroreceptors are an extension of the lateral line system, and as such likely express Usher genes. A ‘fish version of Usher syndrome’ would be hard to come by outside the laboratory, though. The inner ear and lateral line defects that result when an Usher gene is mutated cause pretty dramatic swimming defects, and the fish usually die a few days after hatching because they are unable to locate food.

    Helioprogenus@4: The tissues that will become sensory organs are indeed specified and patterned with a similar genetic toolkit containing a number of transcription factors including some homeobox genes (note that these are not THE Hox cluster genes that I think Shubin was discussing.) I will discuss more about important molecules for development and function in Part II, so stay tuned.

    Skepcanuck@5: Thanks so much for your comment, and I’m pleased to hear the cochlear implants are a success–it’s amazing what a difference they can make. I have talked to a few folks at FFB regarding my work and they are generally well respected within the eye research community, so I personally would feel good about supporting them. Most of the molecular stuff I do is a little too basic for their funding parameters, but our lab has recently applied for a small grant to test a potentially clinically-applicable technique. Aside from donating to research efforts (thanks, by the way!), perhaps there is a deaf-blind community organization near you that could use your support?

    clamboy@6: thanks for the suggestion, I’ll see if I can work it in down the line.

    Stefan@7: the similarities between the two cell types discussed in this post and the ‘common ancestor’ link I provided address this issue. For further reading here on Pharyngula, type ‘Detlev Arendt’ into the search engine on the left.

  12. #12 Monado
    August 13, 2008

    I’ve read (Oliver Sacks?) that it’s almost impossible to lie in sign because you’d have to make your body language lie.

  13. #13 Bobber
    August 13, 2008

    I know I had a hard time hiding my actual intent when signing. More than once I’d try to be “signing calmly” but my deaf girlfriend would say, “But why is your expression angry?”

    Also, it’s hard to “whisper” when someone can read your signs from 30 feet away! : )

  14. #14 Louise Van Court
    August 14, 2008

    Danio, thanks for the science post. I’m just curious about which cellular structures are irreparably damaged by the sound of a shotgun blast (or other extremely loud sound) at close range? Is it the stereocilia, the kinocilium or both, or something else? Does the whole cell then die?
    I will be interested to read the next post about the pathology of Usher syndrome.

  15. Amazing. But I would like to suggest one revision. Delete the word “evolved” in the following sentence.

    In order to intercept and convey information at this level of specificity, sensory cells have evolved specialized structures to meet the high demands of both input and output.

    or you could replace “have evolved” with “were designed with”

  16. #16 Rheinhard
    August 14, 2008

    Not to change the subject (which of course means I’m about to mention something off-topic) but all good Pharyngulans and cephalopodophiles shall go and immediately check out the awesum and funny French student CGI animated short OKTAPODI!

  17. #17 DeafScientist
    August 14, 2008

    I’ll be following your part two, too. (Nice alliteration (of sorts) in that: reminds of some lines from the little birds in Asterix, but lets not get side-tracked!)

    I keep meaning to look back into deafness genes to see if there is any computational modelling or bioinformatics or the like for me to play with, but I keep getting distracted with other ideas.

  18. #18 Zibb
    August 14, 2008

    (Off-topic)

    The cracker episode has been commented on by Andrew Brown in the UK Guardian:
    The discussion of religious differences online is not a game

  19. #19 clinteas
    August 14, 2008

    //The cracker episode has been commented on by Andrew Brown in the UK Guardian://

    Yawn.
    So far,so irrelevant.
    We return you to your regular broadcast.

    And shit,I find myself argeeing(in parts) with Randy :

    //Amazing. But I would like to suggest one revision. Delete the word “evolved” in the following sentence.

    In order to intercept and convey information at this level of specificity, sensory cells have evolved specialized structures to meet the high demands of both input and output.
    //
    or you could replace “have evolved” with “were designed with”//

    The “were designed with” bit is Randy’s usual delusion,but I would agree that “have evolved” is not the right term here,it gives the false impression of a purposeful process,when in reality it would have been natural selection from random mutations that brought about those structures.

  20. #20 Jynx
    August 14, 2008

    “Usher syndrome is a genetically recessive condition characterized by hearing impairment,”

    And before you know it you start listening to lame R’n'B.

  21. #21 BionicAtheist
    August 14, 2008

    Any chance you could go over Waardenburg Syndrome as well? I’m a bit biased toward it seeing as I manifest the hearing impairment from it.

  22. #22 Danio
    August 14, 2008

    Nobody @8: yeah, hard science posts tend to get about 10% of the activity of the controversial posts around here, but they’re worth doing nonetheless. Thanks for stopping by.

    Randy@14: Changing the words won’t change the fact. Evolution happened, is still happening, and will continue to happen.

    Louise@15: Noise damage affects the stereocilia. Loud noises can purturb the organization of the hair bundles, which, if it doesn’t kill the cell outright can impair cell function and contribute to hearing loss. (nb. the kinocilium is a transient structure in mammals. It plays a role in development and then disappears)

    Reinhard@16: Message received. Cthulhu be praised! May you and yours be eaten first.

    Clinteas@19: point taken; change made. Thanks.

    Bionic Atheist @21: I’m really more of a retina gal, but obviously with Usher syndrome it’s important to consider the ear as well. Waardenburg’s is an interesting genetic story as well, so if PZ gives me another Guest Blog spot at some point I may take it on.

  23. #23 K. Signal Eingang
    August 14, 2008

    Sad this sort of thing doesn’t get as much attention as nailing a cracker to a banana peel does… Well-written and I like how you ended on a cliffhanger. I eagerly await part II!

  24. #24 LisaJ
    August 14, 2008

    Really nice post Danio. Your research sounds very exciting. Can’t wait for part 2!

  25. #25 Dr. C.
    August 14, 2008

    neurotransmitters are released into the synapse, imparting a graded, refined message to the waiting second order neurons.

    I thought the action potential was an either/or response, not a graded response.

  26. #26 watercat
    August 14, 2008

    Exciting stuff, and it bears on an unanswered question. My research with signed languages indicates that our brains process both visual and aural languages the same way. Since signed languages are phonologically organized as well as visual, it is too simplistic to describe input to short-term memory in the typical way as being of two distinct types: visual-spatial information and phonological, aural information. It is simultaneously +/- phonological and +/- aural.

    The input to the cortex is basically the output of the neurotransmitters, which is neither aural nor visual, so it may not matter what medium the language used. My question is whether or not the ‘graded, refined message’ that is the output of these two types of neurotransmitters is different at all, and if so different in any way relevant to phonology?

  27. #27 Danio
    August 14, 2008

    Dr C @ 25: (quoting myself):

    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

    You are right that an action potential is on/off. However, as a binary situation–i.e. ‘it’s light!’ or ‘it’s dark!’–would be insufficient to convey the wealth of sensory information coming in, these cells use the graded release method instead.

  28. #28 Phillip Allen
    August 15, 2008

    I join the others in appreciation of this post, and in the anticipation of it’s further development.

  29. #29 pastbyer
    August 15, 2008

    Great post! As a fledgling optometrist I don’t know much about the detailed cellular structure of the hearing system, but I would like to point out an error here:

    “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.”

    Actually, at least for photoreceptors, they release neurotransmitters constantly in the dark, and reduce neurotransmitter release in the light. More light = less neurotransmitter (it’s glutamate, for anyone who’s curious). So the signal works in reverse to what intuition suggests, and photoreceptors actually “detect darkness” (or maybe that’s what you meant?). I’m sure you can imagine how big of a pain this is for people like myself who have to memorise this stuff. The wonders of evolution, eh?

  30. #30 Danio
    August 15, 2008

    pastbyer– chalk it up to editorial license. It just didn’t seem like the right place to go into the various depolarized/hyperpolarized states of the photoreceptors and their posse of second order neurons, so I went with a generic ‘environmental signal’ which, in the case of photoreceptors, is ‘darkness’. It’s hard to make everyone happy with as broad an audience as the Pharyngula readership–PZ does it SO much better.

    BTW, my Hubby is an Optometrist also–IU-Bloomington ’98. Are you still in school?

  31. #31 Danio
    August 15, 2008

    watercat @26, that’s a really interesting question. In terms of the type of neurotransmitters, visual and auditory sensory neurons both use Glutamate to signal their second order neurons. In the retina, bipolar cells, horizontal cells and ganglion cells recieve and refine the signal before it travels through the optic nerve to the visual cortex of the brain. Auditory neurons in the brain use a few different types of neurotransmitters which do seem to be associated with the specific nature of the information they’re receiving from the hair cells. Additionally, the spatial distinctions between individual cells in either the retina or the cochlea can convey information about the nature of the light being ‘seen’ or the frequency of the sound being heard.

    Beyond that, your question delves into issues of higher brain functions that go pretty far beyond the input system. Helen Neville’s work here at the UO on language processing would be interesting to check out if you’re not already familiar with it, and on the molecular side of things, a recent paper in Neuron by Lu and Rubio has some new findings about auditory neuron function.

  32. #32 Mark
    August 22, 2008

    Excellent article. To answer an earlier question about donations, the FFB is great. The majority of retinal breakthroughs in the last several decades have in part been funded by the FFB. HearSeeHope is another organization that raises money specifically for Usher Syndrome research. They are at http://www.hearseehope.com. Finally, if you want to learn more about Usher and other research being done, check out the Coalition for Usher Syndrome Research at http://www.usher-syndrome.org.