If you’re reading this on your laptop right now, say over a Venti Latté at Starbucks, take your hand off the hot cup and lay your fingertips for a moment on the keyboard. You may feel the hard drive spinning, or the fan blowing. Your ability to detect heat and vibrations is due to the presence of different types of nerves in your fingertips. A recent finding by the labs of Carmen Birchmeier and Gary Lewin published in the current issue of Science, shows that a molecule that directs the development of nerve cells is important for the detection of vibrations. This molecule determines the form this nerve cell acquires, its functions in the nervous system, and ultimately whether humans sense high-frequency vibrations. With the findings, the lab has managed to tell a complete story of how the development and function of the nervous system of an organism as a whole can be directly linked to a molecule at work in one of its cell types.
Before scientists can study different kinds of nerves, their functions in organisms, and their roles in disease, they need a way to tell them apart. Hagen Wende and other members of Carmen’s lab first carried out a screen to try to find molecules that could be used to make fine distinctions between types. They discovered that a sub-group of mouse peripheral neurons located in dorsal root ganglia (DRG) produced a protein called c-Maf. Some of the cells expressed this molecule, along with another protein called Ret, at a very early stage. They continued to produce both molecules during the embryonic development of the mouse and after birth.
Some DRG neurons were already known as mechanosensors – transmitters of touch, pressure and vibration sensations – and Hagen and his colleagues wondered about the role of this subset of cells that produced c-Maf. One way to find out would be to “knock out” the c-Maf gene using genetic engineering techniques. Since blocking the production of c-Maf throughout the embryo is lethal – c-Maf has vital functions in other cells – the scientists used a “conditional” knock-out method that removed it only in DRG neurons. The next step was to investigate the effects of this procedure on nerves and the animals’ perception of sensory stimuli.
First they discovered differences in a group of neurons in the DRG: these neurons no longer had thick axons – the trunk-like structures that transmit signals to other nerves. Some of those cells end in thick, egg-shaped ends called Pacinian corpuscles, which detect sensations like pressure and vibration. The corpuscles were much smaller when c-Maf was absent.
“Measurements done by Stefan Lechner in cell cultures showed that the change profoundly disrupted the neurons’ functions,” Carmen says. This effect was very strong in cells called rapidly-adapting mechanosensors (RAMs), which respond to the movement of skin rather than pressure.
Did the changes in mouse neurons correspond to similar effects in humans? “c-Maf also plays a role in the development of the eye – particularly the lens,” Carmen says. “Families with mutations in c-Maf were known to have developmental abnormalities in the eye. But their sensitivity to vibrations had never been tested.”
The researchers contacted one of these families, in whom four people carried the mutation, and tested their ability to detect vibrations. They discovered that the carriers had to be stimulated much more strongly to detect high-frequency vibrations like those produced by the spinning hard drive of a computer, whereas their sensitivity to lower, rumbling vibrations was not affected. And family members without the mutation could detect both types of sensations at normal levels.
Further experiments provided a biochemical explanation of the way changes in c-Maf affected cells. The scientists discovered that the neurons weren’t activating genes called Ret or crystallins (which are crucial in the development of the eye and its lens). They also produced smaller-than-normal amounts of a membrane channel protein called Kcnq4. Gary’s lab has collaborated with the group of Thomas Jentsch at the MDC and FMP to show that this molecule, which permits a flow of potassium ions through the membrane of nerves, plays an important role in the function of mechanoreceptors.
“This provides a full picture of the way c-Maf directs the development of rapidly-adapting mechanosensory nerves by targeting other genes,” Carmen says. “Without it, these cells fail to acquire their proper structure; they lose the Pacinian corpuscles which are needed to ‘fire’ the cells and transmit a signal on to the brain. And humans lose their sensitivity to high-frequency vibrations.”
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