Scientific Understanding of Consciousness
Sense of Touch
Science 16 March 2012: Vol. 335 no. 6074 pp. 1373-1376
The Transcription Factor c-Maf Controls Touch Receptor Development and Function
Hagen Wende1, Stefan G. Lechner2, Cyril Cheret1, Steeve Bourane3, Maria E. Kolanczyk1, Alexandre Pattyn4, Katja Reuter1, Francis L. Munier5, Patrick Carroll4, Gary R. Lewin2, Carmen Birchmeier1
1Developmental Biology, Max Delbrück Center (MDC) for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
2Molecular Physiology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
3Molecular Neurobiology Laboratory, Salk Institute, La Jolla, CA 92037, USA.
4INSERM U.1051, 80 Rue Augustin Fliche, 34091 Montpellier cedex 05, France.
5Jules Gonin Eye Hospital, Avenue de France 15, 1004 Lausanne, Switzerland.
The sense of touch relies on detection of mechanical stimuli by specialized mechanosensory neurons. The scarcity of molecular data has made it difficult to analyze development of mechanoreceptors and to define the basis of their diversity and function. We show that the transcription factor c-Maf/c-MAF is crucial for mechanosensory function in mice and humans. The development and function of several rapidly adapting mechanoreceptor types are disrupted in c-Maf mutant mice. In particular, Pacinian corpuscles, a type of mechanoreceptor specialized to detect high-frequency vibrations, are severely atrophied. In line with this, sensitivity to high-frequency vibration is reduced in humans carrying a dominant mutation in the c-MAF gene. Thus, our work identifies a key transcription factor specifying development and function of mechanoreceptors and their end organs.
Low-threshold mechanoreceptors respond to innocuous mechanical stimulation and are crucial for touch sensation. Mechanoreceptors are physiologically and morphologically diverse and are classified as rapidly adapting, slowly adapting, and D-hair mechanoreceptors (RAMs, SAMs, and D-hairs) on the basis of responses to sustained stimuli and conduction velocities. RAMs/SAMs and D-hairs have large- and medium-diameter myelinated axons, respectively, and are further distinguished by their end-organ morphology. Pacinian corpuscles, Meissner corpuscles, and lanceolate endings are RAMs, whereas Merkel cell-neurite complexes and Ruffini corpuscles are SAMs. Distinct mechanoreceptors detect different stimuli, for example, high- or low-frequency vibration, movement, or static skin indentation. Mechanosensory neurons in dorsal root ganglia (DRGs) derive from neural crest cells, but little is known about their molecular characteristics and development. Low-threshold mechanoreceptors and proprioceptors are born during an early neurogenic wave and depend on the basic helix-loop-helix transcription factor Ngn2 for their generation. The tyrosine kinase receptor Ret is expressed in early- and late-born neurons. Recent work showed that “early Ret” neurons are RAMs and depend on Ret for their development. RAMs also express the transcription factor MafA; however, mutation of MafA has little impact on these receptors. The Maf family encodes basic leucine-zipper factors, whose founding member, v-Maf, was identified as a retroviral oncogene. We show that c-Maf/c-MAF, a gene known to control eye and lens development, is crucial for mechanosensory function in mice and humans.
Our analyses show that c-Maf directs mechanoreceptor development. c-Maf acts upstream of Ret, a receptor known to control RAM development, providing a mechanistic basis for this phenotype. c-Maf and MafA are similar in structure and might act redundantly. The fact that MafA expression is not maintained in c-Maf mutant mechanoreceptors can explain the salient function of c-Maf. c-Maf controls many parameters of RAM development, morphology, and function and modulates functional aspects of SAMs. Our analysis also reveals that the most strongly affected RAM subtype in the c-Maf mutant mice are Pacinian corpuscles that specialize in the detection of high-frequency vibration. Pacinian corpuscles and associated axons were largely absent, and residual corpuscles exhibited disrupted morphologies. Because the deformation of the lamellar end organ of Pacinian corpuscles initiates axonal firing, remaining corpuscles are expected to be functionally impaired. In line with this, humans carrying a dominant cataract-causing c-MAF mutation displayed reduced acuity to high-frequency vibration. Other mechanisms like aberrant spinal processing of vibrotactile information might also contribute to this deficit in humans. We conclude that the transcription factor c-Maf directs RAM development and formation of RAM mechanoreceptive end organs.
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