Assembly, plasticity, and stability of neural circuits
Normal behavioral functions rely on precise and complex neural circuits linking large ensembles of neurons. In development, axons and dendrites extend in a highly directed manner and elaborate intricate branches and arbors to establish organized patterns of 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 appropriate functional synapses. Neural activity shapes circuit development and coordinate with the genetic program.
After the nervous system matures, certain areas of nervous system remain highly plastic in adulthood, whereas others are much less malleable. The regenerative ability of the adult central nervous system is generally highly limited. Abnormal circuit development and degenerative disorders lead to behavioral deficits.
We study development, degeneration and repair of neural circuits.
1. Molecular and Cellular Mechanisms of Axon Guidance
Guidance cues specifying axonal organization
Axonal 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. Using a number of axon model systems, spinal cord commissural neurons, dorsal root ganglion neurons, retinal ganglion cells, corticospinal tracts, and serotonergic and dopaminergic neurons in the brainstem, we are identifying guidance molecules and characterizing their roles in controlling the direction of growth in vivo. We study the function of several families of axon guidance molecules, including the Wnt family proteins, which are conserved directional cues. Gradients of molecular guidance cues, such as the Wnt gradients, control the direction of axon navigation in vivo. Many gradients appear to be at least in part created by their graded gene expression across embryonic structures. We are interested in the mechanisms establishing and maintaining these gradients.
Signaling pathways that guide axons
The growth cone is a specialized structure localized at the tip of a growing axon responsible for sensing and responding to the guidance cues present in its micro-enviroment. Guidance molecules are detected by receptors on the surface of growth cones. Once the cues bind to their receptors, signals are then transduced across the plasma membrane and interpreted in the growth cones. We found that signaling pathways that specify the apical-basal and planar cell polarity of epithelial cells mediate Wnt signaling in axon guidance. We are currently studying how these two cell polarity signaling pathways interact with each other in growth cone guidance.
Axons often face multiple guidance molecules and need to integrate signaling activities to make correct guidance decisions. For axons that travel a long distance, they often have complex trajectories that are made of segments punctuated by intermediate targets before they reach their final target area. Growth cones often stay at the intermediate targets for certain period of time, change their responsiveness and become sensitive to new guidance cues when they leave the intermediate targets. We are studying how growth cones integrate signaling pathways activated by different guidance cues and how their sensitivity to guidance cues change while growing across intermediate targets. We found a classic morphogen, Sonic Hedgehog can switch on responsiveness of commissural axons to Semaphorin at the midline.
Cell biology of growth cone turning
For growth cones to turn in response to guidance molecules, certain directed or asymmetrical processes within the growth cone need to be engaged. It is well known that the cytoskeleton and the growth cone membrane undergo significant reorganization, presumably regulated by signals activated by guidance molecules. But little is known about how these changes cause growth cone turning. We are using the Wnt family guidance molecules as a model system to study the fundamental cellular machinery responsible for growth cone turning and to understand how this machinery responds to guidance cues. One approach we are taking is to identify the key downstream signaling components that regulate cytoskeleton and membrane trafficking, determine their localization and activation in the growth cone and study how these signal activations correlate with changes in cytoskeletal and membrane dynamics. For this, we are using live imaging techniques combined with biochemistry and molecular biology approaches. We found that planar cell polarity signaling component, Vangl2, is enriched in tips of growing filopodia but not in tips of shrinking filopodia, suggesting that the growth cone filopodia tips are the most sensitive part of the growth cone.
2. Wiring for Function
The connections among many areas of the nervous system are highly specific and organized. Part of the organization is set up during pathfinding where axon-axon interactions self sort each other and directional cues lead them to proper target area. Once axons arrive at the target area, they need to establish various patterns of synaptic connections by seeking out correct post-synaptic partners. One type of synaptic connection pattern is topographic connections, which convey smooth and continuous positional information between two connected areas. Our studies suggest that diffusible guidance cues, such as Wnts, also play a role in specifying topographic position by controlling axon target selection. We found that Wnt3 and EphrinB1 are two counterbalancing mapping forces in retinotectal projections along the dorsal-ventral (medial-lateral) axis. We are currently testing whether this "two-molecular-gradient model" is a general mechanism for topographic mapping and how two opposing mapping activities lay out topographic connections. Another common wiring strategy is laminar-specific targeting. For example, different retinal ganglion cell axons find their synaptic targets in different recipient layers in the optic tectum (in chick) and superior colliculus (in mammals). Layer-specific targeting contributes significantly to the specific patterns of synaptic connections and creates cellular and subcellular precisions, which are essential for encoding behavior. We are investigating the mechanisms of this level of brain wiring to understand how functional neural circuits emerge from the molecular cues and their potential interactions with neural activity in this process.
3. Injury and Regeneration of the Mammalian Central Nervous System
In the adult mammalian central nervous system axons generally do not naturally regenerate. We are interested in understanding the mechanisms regulating axon regrowth and regeneration and how these mechanisms could be used to repair the injured central nervous system. Traumatic injury in the central nervous system leads to changes of gene expression in the injured areas as well as in neurons whose connections are altered. Some of these induced genes are important regulators of developmental processes, such as axon guidance. However, the roles of these reinduced developmental genes in injury response are unclear. We are studying the role of reinduced Wnt signaling system in injury response, including regulating axon regeneration. The reinduec Wnt inhibitory system also limits sensory axon regeneration even after conditioning lesion, suggesting that Wnt-Ryk signaling is a general barrier for axon regeneration in the central nervous system. Our final goal is to develop therapeutic approaches to promote regeneration and functional recovery after spinal cord injury.
4. Mechanisms of Neurodegenerative Disorders
Axon loss in degenerative disorders or traumatic injury leads to permanent changes/loss of circuits and function, making it challenging to improve function in affected patients. Because in the mammalian central nervous system axons generally do not naturally regenerate, another approach to try to prevent, or treat neurodegenerative disorders would be by protecting the existing neurons and axons, and impeding their degeneration. In this respect, we are studying the mechanisms that control axon stability and protection, as well as the ones that lead to axon degeneration in several neurodegenerative disease models, such as amyotrophic lateral sclerosis (ALS) and traumatic injury. Our aim is to understand the neurobiological mechanisms that regulate the stability of axons with the aim to develop new therapies for axon protection.
Yimin Zou (2012). Does planar cell polarity signaling steer growth cones? Curr. Top. Dev. Biol. 101:141-160.
Edmund Hollis II and Yimin Zou (2012). Reinduced Wnt signaling limits regenerative potential of sensory axons in the spinal cord following conditioning lesion. Proc. Natl. Acad. Sci. USA 109(36):14663-14668.
Edmund Hollis II and Yimin Zou (2012). Expression of the Wnt signaling system in central nervous system axon guidance and regeneration. Front. Mol. Neurosci. 5:5.
Yimin Zou (2011). When it is hard to get to with genetics--planar cell polarity under a chemical scalpel. Chem. Biol. 18(11):1350-1351.
Beth Shafer, Keisuki Onishi, Charles Lo, Gulsen Colakoglu, Zou Y. (2011). Vangl2 promotes Wnt/planar cell polarity-like signaling by antagonizing Dvl1-mediated feedback inhibition in growth cone guidance. Devel. Cell 20(2):177-191.
Ali G. Fenstermaker, Asheeta A. Prasad, Ahmad Bechara, Youri Adolfs, Fadel Tissir, Andre Goffinet, Yimin Zou, and R. Jeroen Pasterkamp (2010). Wnt/Planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem. J. Neurosci. 30(47):16053-16064.
Barry J. Dickson and Yimin Zou (2010). Navigating Intermediate Targets: The Nervous System Midline. Cold Spring Harbor Perspectives in Biology. Published in Advance June 9, 2010 (doi: 10.1101/cshperspect.a002055).
Liseth M. Parra and Yimin Zou (2010). Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing. Nature Neurosci. 13:29-35 (doi:10.1038/nn.2457).
Esther Stoeckli and Yimin Zou (2009). How are neurons wired to form functional and plastic circuits? Meeting on Axon Guidance, Synaptogenesis and Neural Plasticity (Cold Spring Harbor Laboratories). EMBO J. 10(4):326-330.
Yimin Zou (2009). Axons find their way in the snow. Development 136:2135-2139.
Elizabeth K. Davis, Yimin Zou, and Anirvan Ghosh (2008). Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation. Neural Development 3:32.
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. J. Neurosci. 28:8376-8382.
Patricia C. Salinas and Yimin Zou (2008). Wnt Signaling in neural circuit assembly. Annu. Rev. Neurosci. 31:339-358.
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. J. Neurosci. 28:3456-3467.
Yimin Zou and Anya I. Lyuksyutova (2007). Morphogens as conserved axon guidance cues. Curr. Opin. Neurobiol. 17:22-28.
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). J. Neurosci. 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 Neurosci. 8(9):1151-1159.
Yimin Zou (2004). Wnt signaling in axon guidance (review). Trends Neurosci. 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.