Dr. Guofa Liu's Research
The human brain possesses approximately 1011 neurons and 1014 synapses forming an extraordinarily complex and highly precise network. The formation of proper neural circuitry relies on appropriate neuronal migration, axon guidance and synapse formation during neural development and following injury. Defects in axon guidance and neuronal migration are implicated in a variety of brain disorders, such as lissencephaly, double cortex, periventricular heterotopia, epilepsy, autism, schizophrenia, dyslexia, Alzheimer’s disease, Parkinson’s disease, stroke, traumatic brain injury and spinal cord injury. We are interested in studying the molecular mechanisms underlying neuronal guidance with a goal of providing better therapeutic interventions for central nervous system (CNS) disorders such as stroke and spinal cord injury.
Our research interests lie in three areas:
Intracellular signal transduction cascades mediating neuronal guidance. Coordination of different guidance cues, their receptors and intracellular signal transduction cascades is crucial for neurons to find their targets and establish distinct neuronal circuits. Netrin-1 is a prototypical guidance cue for projecting axons and migrating neurons. We are currently untangling: 1) the collaboration of different Netrin receptors in axon elongation, branching and guidance; 2) the coordination of downstream signaling cascades of Netrin receptors; 3) the coordination of Netrins with other guidance cues, such as Semaphorins, Slits and ephrins, in the developing nervous system.
Cytoskeletal modulation in neuronal guidance. Modulation of actin and microtubule (MT) dynamics in the growth cone of neurons plays a crucial role in axon guidance and neuronal migration. However, whether MT dynamics is directly or directly involved in these processes is unclear. Our recent studies have suggested a novel working model that guidance receptors directly couple MT dynamics in neuronal guidance. We are currently investigating how guidance cues modulate MT dynamics through coupling of their receptors with MT subunits in attractive and repulsive signaling.
Axon outgrowth and regeneration. Axon regeneration is essential for re-establishing neural circuitry and recovery of nerve functionality after injury. The intrinsic ability for axon regeneration in the mature mammalian CNS after injury is extremely limited. An understanding of signal transduction cascades downstream of guidance cues will help us to design promising therapeutic strategies to promote axon regeneration and rescue defects in axon guidance and neuronal migration after CNS injury. Multiple signal transduction cascades have been found involved in promoting axon outgrowth, branching and neuronal migration. We are interested in identifying key players in these pathways in order to provide new treatment strategies for restoring neural function after CNS injury.
Current Laboratory Grants
NIH/NICHD R15 HD-080512-01 Title: Microtubule Dynamics in Axon Outgrowth and Guidance.
Huang H, Shao Q, Qu C, Yang T, Dwyer T, and Liu G (2015). Coordination Interaction of Down Syndrome Cell Adhesion Molecule and Deleted in Colorectal Cancer with Dynamic TUBB3 Mediates Netrin-1-Induced Axon Branching. Neuroscience 293: 109-122. (Cover Illustration)
Liu G and Dwyer T (2014). Microtubule Dynamics in Axon Guidance. Neuroscience Bulletin 30(4): 569-83. (Invited review)
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. (2010). 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).