Molecular markers of mechanoreceptive sensory neurons
Final Report Abstract
The aim of the present project was firstly to characterize in detail the role of the low threshold calcium channel protein CaV3.2 in mechanoreceptors of the dorsal root ganglia (DRG). We showed that this protein has a highly restricted expression pattern in the DRG and up until now this protein is the only known marker for a sub-population of mammalian mechanoreceptors or touch receptors. Using CaV3.2 mutant mice we showed that this calcium channel is involved in regulating the excitability of a specific group of mechanoreceptors. We also generated two mutant knock-in models which should enable us to visualize the development and even morphology of mechanoreceptors that express the CaV3.2 gene. It is important to identify further molecular markers for functionally distinct sub-populations of mechanoreceptors in the DRG as these gene may be direcfiy involved in regulating sensory neuron function but also allow one to study the molecular specification of sensory neuron sub-types. We established two novel experimental models in order to identify such genes and one of these models the neonatal deprivation of NGF was particularly successful. We could show that in mice the phenotypic composition of the DRG was shifted towards more mechanoreceptors after neonatal deprivation of NGF. We screened for changes in gene expression in this model and identified one gene, the tyrosine kinase receptor gene c-Kit, that is expressed in a sub-population of mechaoreceptors and thermal nociceptors. We could show that removal of c-Kit in vivo leads to a reduction the sensitivity f nociceptors to nxious heat. This finding s highly relevant to the clinical situation as anti-cancer drugs have been developed that block the c-Kit receptor. One ofthese drugs which is very widely and successfully used to treat chronic myeloid leukemia (CML) is called Gleevec. We could show in animal models that Gleevec can function as an analgesic drug. Our findings concerning the role of C-kit in the regulation of sensory function were widely reported in the german and international media. Future work will focus on translational aspects of blocking c.kit receplors in humans who are treated in anti-cancer treatment programs.
Publications
- (2004) A plethora of painful molecules. Curr Opin Neurobiol 14:443-449
Lewin GR, Lu Y, Park TJ
- (2004) Mechanosensation and pain. J Neurobiol 61:30-44
Lewin GR, Moshourab R
- (2004) Role of T-type calcium current in identified d-hair mechanoreceptor neurons studied in vitro. J Neurosci 24:8480-8484
Dubreuil AS, Boukhaddaoui H, Desmadryl G, Martinez-Salgado C, Moshourab R, Lewin GR, Carroll P, Valmier J, Scamps F
- (2006) A role for T-type Ca2+ channels in mechanosensation. Cell Calcium 40:165-174
Heppenstall PA, Lewin GR
- (2007) Nociceptive tuning by stem cell factor/c-Kit signaling. Neuron 56:893-906
Milenkovic N, Frahm C, Gassmann M, Griffel C, Erdmann B, Birchmeier C, Lewin GR, Garratt AN
- (2007) Roles for the pro-neurolrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci 10:1449-1457
Jansen P, Giehl K, Nyengaard JR, Teng K, Lioubinski O, Sjoegaard SS, Breiderhoff T, Gotthardt M, Lin F, Eilers A, Petersen CM, Lewin GR, Hempstead BL, Willnow TE, Nykjaer A
- (2008) Stretching it for pain. Pain 137:3-4
Lewin GR
