Saturday, April 28, 2012

A gene at your fingertips

A gene involved in vibration sensing in the skin.

There has been something of a quiet revolution in the biology of human perception. The sense of self now seems far more complicated and constructed than we previously realized. The five senses are only the beginning of a much more complex system of senses plus cognition that situates us in the world, seeing, tasting, and hearing- yes, but also, gyroscoping, sensing muscle and tendon tone, empath-ing, and, generally, feeling what is going on at many levels.

In the skin, we have numerous sensor and nerve systems, including, hot, cold, heavy pressure, light pressure, sustained pressure, and pain (damage and inflammation), involving over seven different sensory cells or structures, some of which overlap in function, creating quite a menagerie for the physiologist.

A recent paper told a remarkable story of one of these mechanoreceptor structures, a gene that is essential for its development, and the discovery of people missing this gene, with a defect in vibration sensation.

One Pacinian corpuscle, abnormally enlarged.
The Pacinian corpuscle is a 1mm onion-like blob in the skin composed of layers of cells and gels surrounding a nerve ending. It responds to rapid vibration, (40 Hz to 500 Hz), as might come from rubbing a rough surface, potentiated by the ridges of our fingerprints. The researchers were studying genes turned on in the developing mouse nervous system when they saw a gene called c-Maf expressed in the neurons that extend from the spinal cord to several skin sensory structures. They were interested in this gene because it is a member of a family of regulatory genes (which turn other genes on/off) known to have roles in sensory structure and peripheral nervous system development.

This particular gene, however, was only known to participate in eye development, so seeing it expressed in early embryonic sensory nerves was a surprise. I'll note here that this is a reason I would never say that this or any other gene is the gene "for" vibration sensing, or Pacinian corpuscle development, etc. Any biological structure of any complexity is built by many many cooperating genes, and most genes conversely collaborate in several or many biological processes, this being how a small genome of 24,000 genes gives rise to the unimaginable complexity that is us.

Indeed, this gene has other roles in development that are currently unknown, since its complete deletion is lethal in mice. So the researchers created a special genome mutation where the c-Maf gene would be destroyed at a pre-determined stage of development in only a few places, by hooking up a killing gene (cre recombinase) to a promoter from another embryonic-specific gene. The resulting mice were viable into adulthood, though with a few coordination problems. They achieved their point of eliminating expression in sensory nerves, with dramatic alterations in the nerves that feed the Pacinian as well as some other corpuscles

Sensory function in these mice was also impaired, as they found by eavesdropping on nerve firing in response to physical stimulation of the mouse's skin. And finally for the mice, they saw dramatic defects in the Pacinian corpuscles themselves.

Defects in vibration-sensing Pacinian corpuscles in mice lacking the c-Maf gene. Note both fewer corpuscles and the rough shape of those remaining.

Other touch sensory structures, like the Meisnerian corpuscles, where affected, with altered function as well, but the most dramatic effects appeared to be in the Pacinian system.

Turning to humans, the researchers knew that c-Maf mutations exist as a rare genetic disease in humans, (with the gene partially defective; not completely dead), causing cataracts and other eye problems. (Not to mention being an oncogene as well.) They figured on the basis of their mouse results that a subtle defect in touch sensation might also be present, though never reported. The last figure shows that this is the case, as the threshold for the sensation of high-frequency vibration, to which the Pacinian corpuscles are particularly sensitive, is quite blunted, with almost ten-fold less sentitivity in the optimal range of ~250Hz.

Humans with a cMaf mutation and associated genetic syndrome also show defects in touch sensation of high-frequency vibration dependent on the Pacinian corpuscles.

The complexity of our sensory apparatus is remarkable. Slowly elaborated over eons of evolution, we are covered with high-tech instrumentation by which we know and enjoy the world. This paper is one of those small bricks in the edifice of knowing just how that experience comes to pass.

"Economic theory also predicts that for a large enough sum of money there will be economists who will say that the stimulus did not work regardless of what they actually believe to be true."


  1. Great post! The wonders of complexity. I especially like your point about how multiple levels of interacting gene regulation (epigenetics) explains how a revatively small finite set of genes can control the almost infinte variation of human physical and psychological/behavioral development.

  2. Thanks again, Catfish! I could write a whole blog about the meanings of "epigenetics"- whether strictly the intergenerational inheritance of traits not encoded in the DNA sequence, (i.e. by methylation and other marks on the DNA), or what seems to have become the looser meaning of any state of cell development that is heritable by its immediate progeny, typically by stable feedback cycles of transcriptional and other regulation that are normal aspects of organism development.