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Biological Sciences Department Faculty
The human brain possesses approximately 1011 neurons and 1015 synapses forming an extraordinarily complex and highly precise network. Appropriate neuronal migration, axon outgrowth and pathfinding are critical for neurons to find their targets and establish neural circuitry during neural development and following injury. Our research is focused on investigating the molecular mechanisms of neuronal migration, axon outgrowth and pathfinding with the goal of providing better therapeutic interventions for CNS conditions such as strokes and spinal cord trauma.
Netrins, a family of secreted proteins, are critical in guiding neuronal migration and axon projection in the developing nervous system. Our previous studies have highlighted the complexity of molecular mechanisms of netrin signaling: FAK (focal adhesion kinase), Src family kinases, p130CAS (Crk-associated substrate) and DOCK180, a member of a new family of guanine nucleotide exchange factors (GEFs) for Rho GTPases are key components in netrin-1 signaling. We recently have identified Dscam (Down syndrome cell adhesion molecule), a transmembrane protein of the immunoglobulin superfamily,functions as a new netrin receptor required for commissural axon outgrowth and pathfinding.
Several important questions remain unanswered: 1) the downstream signaling pathway of netrin/Dscam; 2) the relationship among different netrin receptors, such as Dscam, DCC and UNC5; 3) the coordination of different signaling molecules, such as FAK, Fyn, p130CAS, DOCK180, Rac1 or Cdc42, in netrin/DCC and netrin/Dscam signaling pathway and how these molecules regulate each other in response to netrin; 4) the cross-talking among Dscam and other guidance cues, such as Semaphorin, Slit, ephrin; 5) the functional role of Dscam in netrin-mediated neuronal migration. To resolve these questions will let us further understand how netrin steer growth cones and generate precise patterns of neuronal wiring in the developing nervous system. We plan to extend these studies by using a series of biochemical, cell biological and molecular techniques, in combination with functional approaches, including chick commissural axon turning assay, primary neuronal culture, in vitro explant and slice cultures, and in vivo assays using the developing chicken and mouse as a model.
Another research in our lab will focus on identifying new signal molecules in axon guidance. By introducing selected siRNAs and/or shRNAs into the neural tube of chicken embryos (Fig. A and B), we will be able to examine the axon outgrowth by the culture of dorsal spinal cord explants and the axon turning by the neural tube turning assay in vitro (Fig. D and E) as well as examine axon projection in vivo by the the 'open-book' assay (Fig. F)
Qu C, Dwyer T, Shao Q, Yang T, Huang H, and Liu G (2013). Direct Binding of TUBB3 with DCC Couples Netrin-1 Signaling to Intracellular Microtubule Dynamics in Axon Outgrowth and Guidance. Journal of Cell Science 126 (14): 3070-3081. (Selected in In This Issue)
Qu C, Li W, Shao Q, Dwyer T, Huang H, Yang T, and Liu G (2013). c-Jun N-Terminal Kinase 1 (JNK1) Is Required for Coordination of Netrin Signaling in Axon Guidance. Journal of Biological Chemistry 288 (3): 1883–1895
Purohit, A.A., Li, W., Qu, C., Dwyer, T., Shao, Q., Guan, K.-L., and Liu, G. (2012). Down Syndrome Cell Adhesion Molecule (DSCAM) Associates with Uncoordinated-5C (UNC5C) in Netrin-1-mediated Growth Cone Collapse. Journal of Biological Chemistry 287, 27126-27138.
Liu G, Li W, Wang L, Kar A, Guan K-L, Rao Y and Wu J (2009). DSCAM Functions as A Netrin Receptor in Guiding Commissural Axon Pathfinding. PNAS 106: 2951–2956
Hagihara K, Zhang E, Ke YH, Liu G, Liu JJ, Rao Y and Feng GS (2009). Shp2 Acts Downstream of SDF-1α/CXCR4 in Guiding Granule Cell Migration during Cerebellar Development. Developmental Biology 334(1):276-284
Li X*, Gao X*, Liu G*, Xiong W, Wu J and Rao Y (2008). Netrin Signal Transduction: Roles of the Guanine Nucleotide Exchange Factor DOCK180 in Attractive Signaling. Nature Neuroscience 11: 28-35(* co-first author).
Liu G, Li W, Gao X, Li X, Park H-T, Jürgensen C, Shin NY, Yu J, He M-L, Hanks SK, Wu J, Guan K-L, Rao Y (2007). p130CAS Is Requried for Netrin Signaling and Commissural Axon Guidance. J Neurosci 27(4):957-968. (Cover Illustration)
Liu G, Beggs H, Jürgensen C, Park HT, Tang H, Gorski J, Jones KR, Reichardt LF, Wu J, and Rao Y (2004). Netrin Requires Focal Adhesion Kinase and Src Family Kinases for Axon Outgrowth and Attraction. Nature Neuroscience 7:1222-1232.
Li W, Lee J, Vikis HG, Lee SH, Liu G, Aurandt J, Shen TL, Fearon ER, Guan J-L, Han M, Rao Y, Hong K, and Guan K-L (2004). Activation of FAK and Src Are Receptor Proximal Events Required for Netrin Signaling. Nature Neuroscience 7:1213-1221.
Liu G and Rao Y (2003). Neuronal Migration from the Forebrain to the Olfactory Bulb Requires a New Attractant Persistent in the Olfactory Bulb. J Neurosci 23:6651-6659. (Selected in This Week in the Journal)
Wong K, Ren X-R, Huang Y-Z, Xie Y, Liu G, Saito H, Tang H, Wen L, Brady-Kalnay SM, Mei L, Wu JY, Xiong W-C, and Rao Y (2001). Signal Transduction in Neuronal Migration: Roles of GTPase Activating Proteins and the Small GTPase Cdc42 in the Slit-Robo Pathway. Cell 107:209-221.
Liu G and Rao Y. Neuronal Migration in the Brain in Gazaniga MS ed. The New Cognitive Neuroscience III: 51-68. (MIT Press, Cambridge, 2004).