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Yimin Zou e-mail: yzou@ucsd.edu
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Mechanisms of nerve system wiring
All behavioral functions rely on precise and often complex neural circuits linking large ensembles of neurons. In development, axons and dendrites extend in a highly directed manner and elaborate intricate patterns of branches and arbors to establish organized synaptic connections. A genetic program plays a profound role in the formation of these networks by specifying neuronal cell types, positioning neurons, guiding axons and dendrites and forming specific functional synapses. Certain patterns of neural activity shape circuit development and coordinate with these processes. My lab studies the molecular and cellular mechanisms of nervous system wiring.
Guidance cues patterning neuronal connections
Neuronal connections are highly organized and precisely patterned. Much of the organization is achieved by the action of a large number of axon guidance cues, which control the direction of axon pathfinding and target selection in development. We are studying essential molecular determinants, particularly extracellular guidance cues, which control the directed pathfinding of axons and specify patterns of synaptic connections. Understanding crucial guidance cues and their functions may help the efforts in neural circuit repair.
Axon pathways are often organized along the major body axes. The Wnt family proteins are conserved directional cues along the longitudinal neuraxis, controlling the proper anterior-posterior pathfinding of axons in vertebrate spinal cord and invertebrate bodies. The coordinated functions of conserved guidance molecules along the dorsal-ventral axis, such as Netrin-1, the Slits and Semaphorins, and those along the anterior-posterior axis, such as the Wnts, establish major axon networks. Are Wnts only responsible for anterior-posterior pathfinding? Are Wnts the only cues along anterior-posterior axis?
Axonal projections are frequently patterned in a topographic manner, conveying smooth and continuous positional information between two connected areas. Diffusible guidance cues, such as Wnts, also play a role in specifying topographic position in vertebrate and invertebrate visual systems, controlling axon target selection. Computational modeling predicts that in each axis, two counterbalancing mapping forces are necessary for establishing topographic maps. We found that, in vertebrates, Wnt3 and EphrinB1 are two counterbalancing mapping forces in retinotectal projections along the dorsal-ventral axis of the visual system. Is the two-molecular-gradient model a general mechanism for topographic map formation? How are opposing mapping activities integrated in axons? What controls the specific patterns of the synaptic connections between the retinal ganglion cell axons and the recipient cells in the optic tectum?
Essential to the patterning of neural circuits is the hypothesis that gradients of molecular guidance cues control direction of axon migration. In the case of a number of axon guidance molecules, their gene expression levels are clearly in gradients across embryonic structures. This graded gene expression may contribute to the formation of gradients of axon guidance molecules, providing directional control of growth during wiring. We are interested the mechanism of establishing and maintaining expression gradients of guidance gene families and the role of gradients by altering these gradients in vivo.
Signaling pathways and growth cone turning
Guidance molecules are detected by receptors on the surface of growth cones, specialized structures at the tips of growing axons. Signals are then transduced across the cell membrane and integrated in the growth cones to make guidance decisions. Axons often face multiple guidance molecules, which trigger their receptor activation. How do growth cones integrate different guidance pathways? Where are the convergent points in signal integration and how are they involved in integration?
To turn towards or away from a gradient of guidance molecules, certain directed or asymmetrical processes within the growth cone need to be established. Cytoskeleton and growth cone membrane undergo significant reorganization, presumably regulated by signals activated by guidance molecules. We are using the Wnt family guidance molecules to study the fundamental cellular machinery required for growth cone turning and how this machinery responds to guidance cues and execute turning. One approach we are taking is to identify the key downstream signaling components mediating the function of Wnts and determine their localization and activation in growth cones using live imaging and how these activated correlated with changes in cytoskeletal and membrane dynamics. A fascinating question is how growth cones can tell small concentration differences and make correct turning decisions.
For axons that travel a long distance, they often have complex trajectories that are made of segments separated by intermediate targets before they reach their final target area. Growth cone often stay at the intermediate targets for certain period of time, change their responsiveness and become sensitive to new guidance cues when they leave intermediate target. How growth cones undergo remodeling as they traverse an intermediate target? Spinal cord commissural axons change responsiveness to several axon guidance cues at the spinal cord midline. What are the mechanisms involved in changing of their responsiveness after midline crossing?
Mechanisms of neuronal migration
Proper neuronal positioning is crucial to circuit development. Several brain disorders display both cell migration and neurite outgrowth defects. Growth cone and cell migration have remarkable similarities and interesting differences. Many axon guidance molecules also play roles in neuronal migration. We are studying the cellular function of proteins that are important for neuronal migration and comparing their function and mechanisms during growth cone migration.
Yaobo Liu, Xiaofei Wang X, Chin-Chun Lu, Rachel Kerman, Oswald Steward, Xiao-Ming Xu, and Yimin Zou. (2008). Repulsive Wnt signaling inhibits axon regeneration after CNS injury. Journal of Neuroscience 28:8376-8382.
Alex M. Wolf, Anna I. Lyuksyutova, Ali G. Fenstermaker, Beth Shafer, Charles G. Lo, and Yimin Zou. (2008). Phosphatidylinositol-3-Kinase-Atypical Protein Kinase C Signaling Is Required for Wnt Attraction and Anterior-Posterior Axon Guidance. Journal of Neuroscience 28:3456-3467.
Zou Y., Lyuksyutova AI. (2007) Morphogens as conserved axon guidance cues. Curr. Opin. Neurobiol. Jan 2; [Epub ahead of print].
Yimin Zou. (2006). Navigating the anterior-posterior axis with Wnts. Neuron. 49(6):787-789.
Adam Schmitt, Jun Shi, Alex Wolf, Chin-Chun Lu, Leslie A. King and Yimin Zou. (2006).Wnt-Ryk signaling mediates medial-lateral retinotectal topographic mapping. Nature 439(7072):31-37.
Lee Fradkin, Gian Garriga , Patricia C. Salinas, John Thomas, Xiang Yu and Yimin Zou. (2005) Wnt signaling in neural circuit development (minireview). Journal of Neuroscience 25(45):10376-10378.
Yaobo Liu, Jun Shi, Chin-Chun Lu, Zheng Bei Wang, Anna I. Lyuksyutova, Xuejun Song and Yimin Zou. (2005) Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nature Neuroscience 8(9) :1151-1159.
Yimin Zou (2004). Wnt signaling in axon guidance (review). Trends in Neuroscience 27(9):528-532.
Yimin Zou, Florian Engert and Huizhong W. Tao. (2004). The Assembly of Neural Circuits (Meeting Report). Neuron 43(2):159-163.
Anna I. Lyuksyutova, Chin-Chun Lu, Nancy Milanesio, Leslie A. King, Nini Guo, Yanshu Wang, Jeremy Nathans, Marc Tessier-Lavigne and Yimin Zou. (2003) Anterior-posterior guidance of commissural axons by Wnt-frizzled signaling. Science 302:1984-1988.
Elke Stein, Yimin Zou, Mu-ming Poo, and Marc Tessier-Lavigne. (2001). Netrin-1 binds DCC to stimulate axon outgrowth and turning independent of adenosine A2B receptor activation. Science 291(5510):1976-1982.
Yimin Zou, Esther Stoeckli, Hang Chen, and Marc Tessier-Lavigne. (2000). Squeezing axons out of the gray matter: A role for slit and semaphorin proteins from midline and ventral spinal cord. Cell 102:363-375.
Hang Chen, Anil Bagri, Joel A. Zupicich, Yimin Zou, Esther Stoeckli, Samuel J. Pleasure, Daniel H. Lowenstein, William C. Skarnes, Alain Chedotal, and Marc Tessier-Lavigne. (2000). Neuropilin-2 regulates the development of select cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 25(1):43-56.
Yimin Zou graduated from Shanghai Fudan University and was a CUSBEA (China and United States Biochemistry Examination and Application Program) student and received his Ph. D. from University of California, Davis and San Diego, in 1995. He did his postdoctoral fellowship at University of California, San Francisco from 1996 to 2000 and was an Assistant and Associate Professor at the University of Chicago from 2000 to 2006. He joined the faculty in July, 2006.
