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GENETICS Receptors Discovered that Direct Rod Cell Development Findings May Shed Light on Blinding Diseases HMS researchers have identified a new and surprising mechanism by which rod photoreceptors--the exquisitely specialized light-gathering cells that line the retina--develop from a pool of undifferentiated precursors. The discovery provides information that someday could lead to new methods of restoring or replacing these delicate cells, which are lost in retinitis pigmentosa and other blinding diseases. Taurine's effect on retinal progenitors had been a longstanding mystery in Connie Cepko's lab. The discovery by Tracy Young (left) that it works through neurotransmitter receptors was "very satisfying," said Cepko. (Photo by Phil Farnsworth) "Problems with photoreceptors cause the majority of the known human blindnesses," said Tracy Young, a graduate student at HMS and lead author of the March 25 Neuron study. Like their photoreceptor cousins the cones, rods are highly fragile. "Rods are especially susceptible to genetic lesions that lead to their demise," said senior author Connie Cepko, HMS professor of genetics. "We are interested in anything to do with making a rod, helping it survive, and understanding why it dies." Like all neurons, retinal cells develop according to an interplay of intrinsic and extrinsic cues. To turn into a rod, for example, a retinal progenitor cell must encounter a set of environmental cues, but it must do so at a time when it is capable of responding. In the early 1990s, David Altshuler, then a student in Cepko's lab, found that by adding the amino acid taurine to immature retinal cells, he could get more of them to turn into rods. Yet it was unclear what was making the cells susceptible to taurine's instructions. Altshuler, now an HMS assistant professor of genetics at Massachusetts General Hospital, suspected that taurine, which is abundant in the developing vertebrate retina, might be working its transforming effects through two neurotransmitter receptors, glycine receptor alpha 2 and GABA(A). It Takes Two Building on Altshuler's work, Young has shown that the two receptors are, in fact, responsible for relaying taurine's message. And they work as a pair--both are needed if a neural progenitor cell is to heed taurine's rod-inducing call. This is the first time that neurotransmitter receptors have been shown to play a role in this early stage of neuronal development. "Problems with photoreceptors cause the majority of the known human blindnesses." --Tracy Young Though neurotransmitter receptors had been observed in the immature nervous system when Altshuler began his work 14 years ago, their early appearance was thought to be in preparation for their adult role of communicating inhibitory messages at the synapse of mature neurons. "They have this adult function, and that is the one that most people have focused on," said Young. Inspired by Altshuler's taurine discovery and by observations that taurine interacts with glycine receptor alpha 2 and GABA(A) receptor, Young decided that for her thesis, she would delve into the question of how, exactly, taurine instructs immature retinal cells to become rods. "I wanted to figure out what made cells competent to respond to taurine," she said. She began by blocking the two receptors with antagonists--strychnine in the case of glycine receptor alpha 2 and bicuculline in the case of GABA(A)--which caused rod production to drop even in the presence of taurine. Conversely, stimulating the receptors with both GABA and glycine instead of taurine boosted the production of rods. Interestingly, adding either glycine or GABA alone did not stimulate rod production. "So you need both receptors activated," Young said. In further tests, she misexpressed the glycine receptor alpha 2. Normally, the receptor is expressed just before birth, which corresponds to a peak in rod development just after birth. Young found that by expressing the glycine receptor alpha 2 at an abnormally early time, she was able to shift peak rod formation to an earlier prenatal period. Blocking the receptor's normal expression with RNAi during the peak postnatal period, she was able to blunt the peak altogether. Expanding Molecular Résumés Young and Cepko believe that glycine receptor alpha 2 and GABA(A) receptor, along with taurine, may play a developmental role beyond the retina. "Both taurine and glycine receptor alpha 2 are expressed in the developing brain, even in regions that do not express the mature form of the glycine receptor," said Young. "The brain is chock full of taurine, and nobody knows what it does," said Cepko. "One role now, we think, is in development." How might the amino acid carry out this role? Young and Cepko believe the mechanism may have to do with calcium signaling. Glycine receptor alpha 2 and GABA(A) are chloride channels. At the mature synapse, they let chloride in, which leads to the expulsion of calcium by other channels, the upshot being that the neuron is inhibited from firing. The researchers believe that the door may swing in the opposite direction during development. Activation of the two receptors causes the retinal progenitor to expel chloride and admit calcium through other channels. Young has been exploring the potential downstream effects of this influx of calcium. Teasing out the strands of this web of interactions could lead to methods for alleviating certain forms of blindness. "For diseases where rods and cones die and you want to replace them, one possibility is to start with retinal progenitor cells. Give them the right signals to become rods and then let them develop in situ after they have been signaled in vitro to become rods," said Cepko. "Of course, you need to know the full repertoire of cues used to instruct those cells. We are working on that." --Misia Landau