X.Z. Shawn Xu, Ph.D. Assistant Professor of Physiology Assistant Research Professor, Life Sciences Institute Ph.D., Johns Hopkins University, 2000 6115A, Life Sciences Institute (734)615-9311 shawnxu-a-umich.edu Visit the Xu Lab

Current Research:  

1)  Neuronal signaling, behavior and drug addiction in the genetic model organism C. elegans.

2)  Calcium signaling.  

 Neuronal signaling, behavior and drug dependence
What are the mechanisms of neuronal signaling that underlie behavior and addiction? How do genes control behavior and addiction?  The complexity of the human nervous system poses an immense challenge to address these questions directly in humans.  Nevertheless, as many biological processes are conserved, studies using genetic model organisms have greatly facilitated our understanding of complex processes in humans.

C. elegans has recently emerged as an increasingly popular genetic model organism for the study of neurobiology for several reasons:  First, unlike the human brain that comprises ~100 billion neurons and ~100 trillion synapses, the C. elegans nervous system is relatively simple and very well characterized, with merely 302 neurons and ~6000 synapses.  Despite such simplicity, C. elegans possesses complex behaviors, and the basic mechanisms of neuronal signaling underlying behavior are well-conserved. Many genes regulating neuronal activity were first cloned in C. elegans, which then facilitated the identification of their homologs in mammals.  In addition, C. elegans represents the only organism whose nervous system has been completely mapped by electron microscopy; namely, we know the wiring and exact location of each neuron.  Furthermore, the wealth and ease of genetic tools available in C. elegans combined with its short generation time (~3 days per generation) and easy propagation offer an unparalleled advantage for isolating mutants, identifying novel genes and studying their functions in vivo.

To understand the mechanisms of neuronal signaling that underlie behavior and addiction, we are taking a multidisciplinary approach involving molecular genetics, imaging, computational modeling, electrophysiology, pharmacology and biochemistry. We are particularly interested in how ion channels, membrane receptors and calcium signaling molecules regulate neural activities.  One of our current focuses concerns the functional roles of an emerging superfamily of calcium-permeable ion channels, the TRP channels, which are conserved from worms to humans. Although mammalian TRP channels have been extensively characterized in vitro, their in vivo biological functions are poorly understood.  We have isolated mutations in several TRP channel genes and found that these channels regulate multiple behaviors.  We are now investigating the mechanisms by which TRP channel-mediated calcium signaling regulates neuronal activity and behavior.

Fertilization and calcium signaling: Sperm-egg interactions
In addition to its role in the nervous system, calcium, a universal second messenger, regulates a plethora of physiological processes ranging from cell death to fertilization.  Fertilization, the first step in development, is triggered by a series of specialized sperm-egg interactions that culminate in gamete fusion.  Despite intense studies, very little is known about the molecular mechanisms of sperm-egg fusion in any organism.  We have identified a sperm-enriched C. elegans TRP channel, TRP-3, and found that mutations in trp-3 lead to sterility because of the inability of mutant sperm to fuse with the egg. These results reveal an unexpected role for TRP channels and calcium signaling in regulating fertilization. We are currently seeking to elucidate the signaling pathways that regulate sperm-egg interactions leading to fertilization.

Representative Publications:

Xu, X.Z.S., Li, H.‑S., Guggino, W.B., and Montell, C. (1997). Coassembly of TRP and TRPL produces a distinct store‑operated conductance.    Cell  89, 1155‑1164.

Xu, X.Z. S., Choudhury, A., Li, X., and Montell, C. (1998). Coordination of an array of signaling proteins through homo- and heteromeric interactions between PDZ domains and target proteins.    Journal of Cell Biology  142, 545-555

Xu, X.Z.S., Wes, P., Li, H.‑S., Yu, M., Morgan, S., Liu Y., and Montell, C. (1998). Retinal targets for calmodulin include proteins implicated in synaptic transmission.      Journal of Biological Chemistry  273, 31297-31307.

Wes P. D., Xu, X.Z.S., Li, H.-S., Chen, F., Doberstein, S. K., and Montell, C. (1999)  Termination of phototransduction requires binding of the NINAC myosin III and the PDZ protein INAD.    Nature Neuroscience  2, 447-453.  

Li, H.-S., Xu, X.Z.S., and Montell C.  (1999)  Activation of a TRPC3-dependent cation current through the neurotrophin BDNF.    Neuron  24, 261-273.

Xu, X.Z.S., Chien, F., Butler, A., Salkoff, L., and Montell, C.  (2000)  TRPg, a  Drosophila TRP-related subunit, forms a regulated cation channel with TRPL.    Neuron  26, 647-657.

Xu, X.Z.S., Moebius, F., Gill, D.L., and Montell, C. (2001) Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.    Proceedings of National Academy of Sciences U.S.A. 98, 10692-10697.

Xu, X.Z.S., and Sternberg, P.W. (2003) A C. elegans sperm TRP protein required for sperm-egg interactions during fertilization.     Cell 114, 285-297.

Li, W., Feng, Z., Sternberg, P.W., and Xu, X.Z.S. (2006) A C. elegans stretch receptor neuron revealed by a mechanosensitive TRP channel homologue.   Nature 440, 684-687.

Feng, Z., Li, W., Ward, A., Piggott, B.J., Larkspur, E., Sternberg, P.W., and Xu, X.Z.S. (2006) A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels.  Cell  127, 621-633

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