罗正和（音译）博士简介

生物谷

Zhenge Luo, Ph.D.

Rm204, SIBS Building
Institute of Neuroscience
Chinese Academy of Sciences
Shanghai 200031
China
Phone: 86-21-5492-1831
Fax: 86-21-5492-1832
Email: zgluo@ ion.ac.cn

Dr. Zhenge Luo is an Investigator and Head of the Laboratory of Synaptic Signaling. He graduated from Nankai University, Tianjin in 1988 and received his Ph. D. from Chinese Academy of Military Medical Sciences(AMMS), Beijing in 1995. He was appointed as associate professor at AMMS in 1998. He received postdoctoral training in the Department of Neurobiology, University of Alabama at Birmingham, USA during 2000-2003. His major research interest is the molecular mechanism of synapse formation in neuromuscular Junction(NMJ)

Research Interests
	Synapses are structural units essential for neuronal communication. Understanding the molecule mechanisms of synapse formation, maintenance, and plasticity is essential for our understanding of the development and functions of the nervous system. The neuromuscular junction (NMJ) is a peripheral cholinergic synapse formed between the motor neuron and the skeletal muscle. Since the NMJ is large in size and easily accessible, studies of the NMJ formation have provided insights into the principles and mechanisms of synaptogenesis in general. We are interested in molecular mechanisms of how postsynaptic membranes differentiate, with a focus on the formation of clusters of acetylcholine receptors (AChRs) in the postjunctional or postsynaptic membrane. Three proteins have been shown to be essential for the formation of the NMJ: MuSK, a muscle specific receptor tyrosine kinase; agrin, a signal produced by presynaptic motor neurons; rapsyn, an intracellular protein that interacts with the AChR. We are currently dissecting the molecular mechanisms associated with the actions of these three proteins in the formation of AChR clustering and other aspects of NMJ formation. Similar neurotransmitter receptor clusters have been observed at CNS synapses. Our studies of AChR clustering at the NMJ may shed light on the process of receptor clustering at central synapses as well. Our long term goal is try to understand the more complicated processes in CNS synaptogenesis, especially the aspect of the coordination between the presynaptic neuron and postsynaptic cell.

	Ongoing Projects
	We have identified Dishevelled(Dvl) and geranylgeranyltransferase I (GGT) as MuSK binding proteins. Our results suggest that MuSK serves as a key scaffold protein for a complex of signaling molecules, termed "signalsome". In our working model, interaction of Dvl with MuSK regulates agrin-induced activation of PAK, a serine/threonine protein kinase known to regulate cytoskeleton organization. Activation of PAK, which is required for AChR clustering, is regulated by Rho GTPases. Interestingly, GGT, an enzyme that tethers proteins to the plasma membrane by prenylation, directly binds to MuSK and appears to regulate Rho GTPases activation and AChR clustering as well. The interactions of Dvl and GGT with MuSK guarantee synapase specific activation of Rho GTPases and PAK, and then AChR clustering. Although extensive studies have been taken to uncover the mechanisms underlying Agrin/MuSK signaling in NMJ synaptogenesis, a number of outstanding questions remain unanswered. For examples, we do not know how agrin-induced signals are transduced from MuSK to rapsyn, through what mechanism rapsyn regulates AChR clustering, whether the Wnt signaling components regulate agrin signaling and vice versa, and how the postsynaptic muscle components, such as MuSK, regulate presynaptic differentiation. Our ongoing projects are being taken to unveil these mysteries. (1)The mechanisms of Rapsyn in NMJ formation. Genetic evidence has shown that rapsyn, a 43-kDa postsynaptic protein, plays an essential role in NMJ synaptogenesis. It is also believed that rapsyn serves at the downstream of MuSK signaling pathway leading to AChR clustering. But how rapsyn participates in agrin/MuSK pathway remains poorly understood. To this end, we have identified Dishevelled and GGT as the components of MuSK "signalsome". Whether rapsyn functions through the regulation of MuSK "signalsome" is a crucial question needs to be answered. The identification of rapsyn binding proteins is the strategy being used. (2)Wnt signaling and synaptogenesis. We have identified Dishevelled(Dvl or Dsh) as a MuSK binding protein. Dvl was originally discovered in Drosophila for its role in the development of coherent arrays of polarized cells. It functions downstream of the Wingless(or Wnt) receptor Frizzled, a family of seven-transmembrane domain proteins. Wnts are a large(>19members) family of secreted proteins that regulate embryonic patterning, tissue polarity, and cell fate decisions. Interestingly, the extracellular portion of MuSK contains a cysteine-rich domain(CRD) which is highly homologous with the Frizzled CRD domain that serves as Wnt binding site. We reasoned that Wnt signaling may regulate NMJ synaptogenesis through either extracellular or intracellular interactions with MuSK signaling cascade. Several pieces of evidence have shown that Wnt(or Wingless in Drosophila) may regulate axonal behavior and synapse formation in CNS. But how Wnt signaling functions in synaptogenesis remains elusive. we will systematically study the temporal and spatial expression of various Wnts and the receptor Frizzled in NMJ and CNS and the possible mechanisms in synaptogenesis. Gain and loss of function strategies will be used to study the involvement of Wnts and signaling proteins, e.g., Dvl, GSK3¦Â, and ¦Â-Catenin, in the process of synapse formation, both in vitro and in vivo. (3) Identification of retrograde signals from skeletal muscle. Assembly of synapses needs the mutual signals coordinating between presynaptic and postsynaptic cells. In the NMJ, postsynaptic muscle cells regulate presynaptic differentiation of motor neuron. Genetic evidence has shown that MuSK is critical for the production or coupling of such a muscle-derived signal that acts retrogradely to induce the differentiation of axon terminals. We have also observed that the disruption of MuSK signaling could cause either abnormal neurotransmitter release or motorneuron over-growth at the NMJ. We are trying to identify this MuSK associated retrograde signal.

	Publications
	Luo, Z., Je, H., Wang, Q., Yang, F., Clem Dobbins, G., Yang, Z., Xiong, W., Lu, B., and Mei, L. (2003) Implication of Geranylgeranyltransfersae in Synapse Formation. Neuron, 40(4): 703-717 Luo, Z., Wang, Q., Xiong, W., and Mei, L. (2003) Signaling complexes for postsynaptic differentiation. J Neurocyt., 32(5-8): 697-708 (Review) Z.G. Luo, Q. Wang, J.Z. Zhou, J. Wang, M. Liu, X. He, A. Wynshaw-Boris, W.C.Xiong, B. Lu, L. Mei. Regulation of AchR clustering by Dishevelled Interacting with MuSK and PAK1. Neuron 2002; 35(3):489-505.(Featured in Neurobiology Paper Alert, Curr. Opinion Neurobiol. 12:463-470, 2002) Hamblet, N., Lijam, N., Ruiz-Lozano, P., Wang, J., Yang, Y., Luo, Z., Mei, L., Chien, K., Sussman, D., and Wynshaw-Boris, A. (2002) Dishevelled-2 is essential for cardiac outflow tract development, somite segmentation, and neural tube closure. Development, 129(24): 5827-5838 Huang, Y., Wang, Q., Won, S., Luo, Z., Xiong, W., and Mei,. (2002) Compartmentalized NRG signaling and PDZ domain-containing proteins in synapse structure and function. Int J Dev Neurosci., 20(3-5): 173-185