research project 1
Molecular Physiology of Somatic Sensation
Professor Gary R. Lewin (Ph.D.)
Somatic sensation includes all those sensations that we consciously feel after stimulation of the body, e.g. touch, warmth, cooling, or even limb movement. We experience these sensations as a direct result of the activation of sensory neurons that are located in the dorsal root ganglia (DRG). In our group we are interested in the molecular mechanisms that allow these neurons to transduce these varied stimuli. Sensory neurons can, for example, detect changes in temperature of the skin in non-noxious (not painful) as well as the noxious range (painful heat, or cold). They can also detect gentle movement of the skin as well as intense mechanical stimulation of the skin that is normally harmful. The nature of the transduction molecules involved together with the developmental events that lead to specification of the appropriate sensory neuron sub-types are actively investigated the lab.
Molecular Basis of Mechanotransduction
Christiane Wetzel, Yinth Andrea Bernal-Sierra, Liudmilla Lapatsina, Stefan Lechner
Mechanotransduction is the process whereby receptor proteins present in the endings of sensory neurons are able to detect mechanical stimulation of the tissue they innervate. We have used information from genetic experiments with the nematode worm C.elegans to identify possible vertebrate candidate proteins that might detect mechanical stimuli. Genetic screens for touch insensitive worms have turned up around 15 genes whose function is necessary to confer touch sensitivity. These genes were named mec for mechanically insensitive and we have focused on identifying a role mammalian orthologs of these genes in touch sensation. The mec genes in C.elegans have been proposed to work together in a mechanotransduction complex. An essential component of this complex is the membrane protein MEC-2 that forms a hairpin in the membrane and might regulate the activity of the mechanotransducing channel. We have cloned new vertebrates homologues of mec genes and have created mouse mutant alleles to characterize the in vivo function of these genes. MEC-2 is a member of a large family of proteins that contain a stomatin-like domain. A member of this family called SLP3 (stomatin like protein-3) was cloned by our group, and we subsequently generated a mouse model with a null mutation of the SLP3 locus. In SLP3 mutant mice many mechanoreceptors (or touch receptors) in the skin do not work in the absence of the SLP3 protein. In order to analyze touch sensation in mice we also developed a novel behavioral assay for touch driven behavior in rodents. This assay is based on the ability of mice to detect and react to gratings, which are fine enough to have a textured quality. We were very pleased to find that SLP3 mutant mice have severe deficits in their ability to detect such textured surfaces. Current work in the lab focuses on the role of related members of the stomatin-domain family in mechanotransduction, structure function studies and the identification of further essential interaction partners for SLP3.
1. Mannsfeldt, A.G., Carroll, P., Stucky, C.L. & Lewin, G.R. Stomatin, a MEC-2 like protein, is expressed by mammalian sensory neurons. Molecular and cellular neurosciences 13, 391-404 (1999).
2. Martinez-Salgado, C., Benckendorff AG, Chiang LY, Wang R, Milenkovic N, Wetzel C, Hu J, Stucky CL, Parra MG, Mohandas N, Lewin GR. Stomatin and sensory neuron mechanotransduction. J. Neurophysiol 98, 3802-3808 (2007).
3. Wetzel, C., Hu J, Riethmacher D, Benckendorff A, Harder L, Eilers A, Moshourab R, Kozlenkov A, Labuz D, Caspani O, Erdmann B, Machelska H, Heppenstall PA, Lewin GR. A stomatin-domain protein essential for touch sensation in the mouse. Nature 445, 206-9 (2007).
4. Lechner SG; Markworth S; Poole K; Smith ES; Lapatsina L; Frahm S; May M; Pischke S; Suzuki M; Ibanez-Tallon I; Luft FC; Jordan J; Lewin GR. The molecular and cellular identity of peripheral osmoreceptors. Neuron 69 (2): 332-344 (2011)
5. Chiang LY; Poole K; Oliveira BE; Duarte N; Bernal Sierra YA; Bruckner-Tuderman L; Koch M; Hu J; Lewin GR. Laminin-332 coordinates mechanotransduction and growth cone bifurcation in sensory neurons. Nature Neuroscience 14(8): 993-1000 (2011-07-03)
6. Heidenreich M; Lechner SG; Vardanyan V; Wetzel C; Cremers CW; De Leenheer EM; Aranguez G; Moreno-Pelayo MA; Jentsch TJ; Lewin GR. KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. Nature Neuroscience : (2011-11-20)
A single sensory neuron growing a check patterned substrate. Top right (A) shows the stripes of laminin printed onto a glass surface. Note that different proteins can be printed in the vertical (red) or horizontal axis (green). (B ) Phase contrast picture of a sensory neuron growing on the patterned substrate. Note that the neuron only grows neurites along the stripes to form a window like pattern of growth. In this picture the neuron was recorded with a patch pipette (RE) and the neurites can be mechanically stimulated with a nanomotor (MS). (C) The neurons was filled with a yellow dye via the recording pipette to show that neurites belong to the indicated cell. (D) Colour combine showing the pattern together with the yellow neurons and its neurites.
Model summarizing the three waves of mechanosensitivity acquisition in different sensory neuron subtypes. Developmental stage is depicted from top to bottom for mechanoreceptors (blue) and nociceptors (red). Cartoons (right) depict the innervation of the limb with the known distribution of the neurotrophins NT-3 and NGF.