Monica Driscoll Professor Rutgers University Dept.of Molecular Biology and Biochemistry Nelson Biological Labs. Room A232 Piscataway. N.J. 08854 (732) 445-7182 FAX - 7192 driscoll@waksman.rutgers.edu

Developmental neurogenetics. molecular genetics of neuronal cell death. mechanosensory transduction in touch and feeling. molecular mechanisms of aging

Maintenance of healthy and functional neuronal populations is critical for human health. Our lab uses the elegant and powerful model system C. elegans to decipher molecular mechanisms of neuronal function and dysfunction. The biological problems we investigate include touch sensation. neuronal degeneration and aging.

Mechanotransduction--Touch and Feeling at the Molecular Level.

One of the looming mysteries in signal transduction today is the question of how mechanical signals. such as pressure or force delivered to a cell. are interpreted to direct biological responses. A long-standing problem in the mechanotransduction field has been that genes encoding mechanically-gated channels eluded cloning efforts. resulting in a large gap in our understanding of their function. We have identified a new family of ion channels (the degenerin channels) that are hypothesized to normally function as the central mediators of touch transduction and proprioception (how the body maintains coordinated movement) in C. elegans. We are currently combining genetic. molecular and electrophysiological approaches to determine and compare the composition/regulation of mechanosensitive complexes in an effort to contribute to the understanding of the function of this newly discovered channel class.

Molecular Mechanisms of Neurodegenerative Cell Death. Various cellular insults. including hyperactivation of ion channels. expression of human b-amyloid protein implicated in Alzheimer's disease. and constitutive activation of certain G proteins can induce a necrotic-like cell death in C. elegans. This suggests that diverse initiating stimuli may induce a common death mechanism in injured cells.We are genetically and molecularly deciphering the C. elegans necrotic death mechanism. Toward this end we have identified several novel genes that are required for necrotic-like cell death. We are currently cloning these genes and determining role in necrosis. Elucidation of the molecular bases of necrotic-like cell death in simple animal models should provide insight into the basic biology of inappropriate neuronal death and facilitate the characterization of mechanisms underlying degeneration in human disorders.

Molecular Mechanisms of C. elegans aging. Several genes that mutate to significantly extend lifespan have been identified in C. elegans. yet little is known about how the animal ages. We have been using cellular markers to study what happens to individual cell types as C. elegans ages. We have found that the nervous system does not dramatically age or degenerate. but muscle deteriorates significantly-a condition similar to human sarcopenia. the progressive muscle loss that accompanies aging. We are dissecting molecular mechanisms of muscle decline using the powerful C. elegans model system.

Selected Publications

Mano I, Driscoll M. (2009) Caenorhabditis elegans glutamate transporter deletion induces AMPA-receptor/adenylyl cyclase 9-dependent excitotoxicity. J Neurochem. 108(6):1373-84.

Wang Y, Apicella A Jr, Lee SK, Ezcurra M, Slone RD, Goldmit M, Schafer WR, Shaham S, Driscoll M, Bianchi L. (2008) A glial DEG/ENaC channel functions with neuronal channel DEG-1 to mediate specific sensory functions in C. elegans. EMBO J. 27(18):2388-99. Erratum in: EMBO J. (2008) 27(19):2638.

Ibáñez-Ventoso C, Vora M, Driscoll M. (2008) Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology. PLoS ONE. 3(7):e2818.

Tsechpenakis G, Bianchi L, Metaxas D, Driscoll M. (2008) A novel computational approach for simultaneous tracking and feature extraction of C. elegans populations in fluid environments. IEEE Trans Biomed Eng. 55(5):1539-49.

Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4(2):e24.

Mano I, Straud S, Driscoll M. (2007) Caenorhabditis elegans glutamate transporters influence synaptic function and behavior at sites distant from the synapse. J Biol Chem. 282(47):34412-9.

Bianchi L, Driscoll M. (2006) Heterologous expression of C. elegans ion channels in Xenopus oocytes. WormBook. Aug 1:1-16. Review.

Bianchi L, Driscoll M. (2006) Culture of embryonic C. elegans cells for electrophysiological and pharmacological analyses. WormBook. Sep 30:1-15. Review.Ibanez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M. (2006) Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell. 5(3):235-46.

Royal DC. Bianchi L. Royal MA. Lizzio M Jr. Mukherjee G. Nunez YO. Driscoll M. (2005) Temperature-sensitive mutant of the Caenorhabditis elegans neurotoxic MEC-4(d) DEG/ENaC channel identifies a site required for trafficking or surface maintenance. J Biol Chem. 280(51):41976-86.

Gerstbrein B. Stamatas G. Kollias N. Driscoll M. (2005) In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell. 4(3):127-37.

Bianchi. L.. Gerstbrein. B.. Frøkjær--Jensen. C.. Royal. D.. Mukherjee. G. Royal. M. Xue. J. Schafer. W.R.. Driscoll. M. (2004). The neurotoxic MEC-4(D) DEG/ENaC sodium channel conducts calcium: implications for necrosis initiation. Nature Neurosci. 7:1337-1344.

Driscoll. M. and Gerstbrein. B. (2003). Dying for a cause: Invertebrate genetics takes on human neurodegeneration. Nature Rev. Genet. 4:181-194.

Thieringer. H.A.. Moller. B.. Dodt. G.. Kunau. W.-H.. and Driscoll. M. (2003). Modeling the human peroxisome biogenesis disorders in the nematode Caenorhabditis elegans. J. Cell Science 116: 1797-1804.

Suzuki. H.. Kerr. R.. Bianchi. L.. Frokjar-Jensen. C.. Sloan. R.. Xue. J.. Gerstbrein. B.. Driscoll. M. and Schafer. W.R. (2003). In vivo functional analysis of C. elegans mechanosensory neurons defines a specific role for the MEC-4 channel in gentle touch sensation. Neuron 39: 1005-1017.

Bianchi. L.. Kwok. S.. Driscoll. M. and Sesti. F. (2003). A potassium channel-MiRP complex controls neurosensory function in Caenorhabditis elegans. J. Biol. Chem. 278: 1241512424.

Herndon. L.A.. Schmeissner. P.. Dudaronek. J. Listner. K.M.. Brown. P.A.. Sakano. Y.. Paupard. M.. Hall. D. and Driscoll. M. (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419: 808-814.

Syntachki. P. Xu. K.. Driscoll. M.. Tavernarakis. N. (2002). Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419: 939-944.

Bianchi. L. and Driscoll. M. (2002). Protons at the gate: DEG/ENaCs help us feel and remember. Neuron 34: 337-340.

Xu. K.. Tavernarakis. N. and Driscoll. M. (2001) Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca²⁺ release from the endoplasmic reticulum. Neuron 31: 957-971.

Driscoll. M. and Tavernarakis. N. (2000). Closing in on a mammalian touch receptor. Nature Neurosci. 3: 7-9.

Chung. S.. Gumienny. T.. Hengartner. M. and Driscoll. M. (2000). C. elegans apoptotic and necrotic cell corpses are removed by activities of a common set of engulfment genes. Nature Cell Biol.2: 931-937.

Hong. K.. Mano. I. and Driscoll. M. (2000). Structure/function analysis of C. elegans mec-4. a component of a Na+ channel required for mechanotransduction. J. Neurosci. 20: 2575- 2588.

Tavernarakis. N.. Wang. S.. Dorovokov. M.. Ryazanov. A. and Driscoll. M. (2000). Heritable and inducible genetic interference by double stranded RNA encoded by transgenes. Nature Genetics 24: 180-183.