Martin Chalfie, Ph.D.
We are using the nematode Caenorhabditis elegans to investigate aspects of nerve cell development and function. The wealth of developmental, anatomical, genetic, and molecular information available for C. elegans provides a powerful and multifaceted approach to these studies. Our work has focused on the study of a set of six neurons that are the sensory receptors for gentle touch (the touch receptor neurons), to address two questions: 1) how is neuronal cell fate determined and 2) what is the molecular basis of mechanosensation, a sensory modality that underlies a variety of senses (e.g., touch, hearing, and balance)? We also work on neuronal degeneration, microtubule structure and function, and channel structure and function.
We initially approached touch development by mutational analysis, obtaining more than 450 mutations (in 17 genes) that produce a touch insensitive phenotype. These touch genes are needed for both development (generation and differentiation) and function of the cells. Many of the genes that regulate touch cell differentiation are transcription factors, including one recently discovered gene whose product appears to insure the differentiated state.. We have also identified seven other genes that further restrict the number and differentiation of the touch receptor neurons. Twelve touch genes are needed for touch receptor neuron function. The cloning and characterization of these genes have provided the first molecular model for eukaryotic mechanosensation. Our recent experiments have used electrophysiological and biochemical methods to demonstrate that a complex of touch cell membrane proteins tranduces touch in these cells. The study of one protein in this complex, MEC-2, has led to the discovery of a new class of cholesterol-binding proteins. These proteins appear to change the local lipid environment of target proteins to regulate their function. Other components of the complex also appear to regulate the local lipid environment. In addition, we have used DNA microarrays and neuron-specific RNAi to identify many more touch cell-specific genes that were not identified in our genetic screens.
2008, Nobel Prize in Chemistry
Chalfie, M. (2009) Neurosensory mechanotransduction. Nat. Rev. Mol. Cell Biol. 10(1):44-52.
O’Hagan, R., Chalfie, M., and Goodman, M. B. (2005) The MEC-4 DEG/ENaC channel of C. elegans touch receptor neurons transduces mechanical signals. Nature Neurosci. 8: 43-50.
Bounoutas, A., O'Hagan, R., and Chalfie, M. (2009) The multipurpose 15-protofilament microtubules in C. elegans have specific roles in mechanosensation. Curr. Biol. 19:1362-1367.
Topalidou, I., van Oudenaarden, A., and Chalfie, M. (2011) The C. elegans aristaless/Arx gene alr-1 restricts variable gene expression. Proc. Natl. Acad. Sci. USA 108: 4063-4068.
Topalidou, I. Keller, C. Kalebic, N., Nguyen, K. C., Somhegyi, H., Politi, K. A., Heppenstall, P., Hall, D. H., and Chalfie, M. (2012) Genetically separable functions of the MEC-17 tubulin acetyltransferase affect microtubule organization. Curr. Biol. 22: 1057-1065.
Zheng, C., Karimzadegan, S., Chiang, V., and Chalfie, M. (2013) Histone methylation restrains the expression of subtype-specific genes during terminal neuronal differentiation in Caenorhabditis elegans. PLoS Genetics 9: e1004017.
Chen, X., and Chalfie, M. (2014) Modulation of C. elegans touch sensitivity is integrated at multiple levels. J. Neurosci. 34: 6522-6536.
Chen, X. and Chalfie, M. (2015) Regulation of mechanosensation in C. elegans through ubiquitination of the MEC-4 mechanotransduction channel. J. Neurosci. 35: 2200-2212.