TSRI scientists have discovered an important mechanism underlying sensory feedback that guides balance and limb movements. The finding, which the TSRI team uncovered in fruit flies, centers on a gene and a type of nerve cell required for detection of leg-joint angles.
The new study identified a new gene and a type of nerve cell required for detection of leg position. This image shows a stum-expressing sensory neuron in a leg joint.
“These cells resemble human nerve cells that innervate joints, and they encode joint-angle information in the same way,” said team leader and TSRI Assistant Professor Boaz Cook. If the findings can be fully replicated in humans, they could lead to a better understanding of, and treatments for, disorders arising from faulty proprioception – the detection of body position.
The proprioceptive sense of how limbs are positioned enables a person to touch the tip of the nose with the tip of a finger, even with eyes closed – an ability easily impaired by alcohol, which is why police often test suspected drunk drivers this way.
Scientists have known that proprioceptive signals originate from so-called mechanosensory neurons, whose nerve ends are embedded in muscles, skin and other tissues. The stretching or compression of these tissues opens ion channels in the nerve membrane, which results in a signal to the brain.
What hasn't been clear is how such a neuron can specialize in sensing just one type of membrane-distorting stimulus – such as the angle of a limb joint – yet exclude others, such as impact pressures.
In the new study, Dr. Cook and two members of his laboratory, first author Bela S. Desai, a postdoctoral fellow, and graduate student Abhishek Chadha, sought to shed some light on this mystery with a study of Drosophila fruit flies. Because they mature quickly, Drosophila are often analyzed for clues to the genetic underpinnings of basic animal behaviors.
Dr. Cook and his colleagues began with a special collection of Drosophila containing a variety of uncatalogued mutations. The scientists looked for mutant flies with walking impairments and zeroed in on several that turned out to have mutations in the same gene. The scientists named the gene stumble (stum for short).
Using a fluorescent tracer, they then localized the expression of stum in normal flies to neurons that lay close to the three main leg joints. Each neuron's input-sensing tendril (dendrite) grew right up to the joints – a sign that its evolved function is detecting joint angle. The researchers also found that the protein specified by the stum gene normally migrates to the tip of each dendrite. With high-resolution microscopy, they imaged each of these tips and observed an extra length branching sideways at the joint.
At ordinary, at-rest joint angles, the relative positions of the main dendrite tip and its side branch stayed relatively the same; however, at extreme joint angles, the pair stretched out. As this happened, the level of calcium ions in the neuron rose sharply, suggesting that ion channels had opened and the neuron was becoming active. Dr. Cook noted the results show how a seemingly general mechanosensory, membrane-stretch-sensitive neuron can evolve a specificity for a particular type of proprioceptive signal.
The team is now trying to nail down the specific role of stum proteins in Drosophila and determine whether the human version also works in joint angle sensing. Some sensory role for the human version is likely, as the stum gene has been well conserved throughout evolution. Dr. Cook and his colleagues were even able to restore some walking ability to stum-mutant flies by adding the mouse version of the stum gene.
“Stum is probably doing the same thing in all animals,” he said.