Huaye Zhang, PhD

Huaye Zhang is an Associate Professor at the Department of Neuroscience and Cell Biology. She completed her PhD and postdoctoral training at the University of Virginia. She provided the following statement about her lab:

Neurons are arguably the most polarized/compartmentalized cell type in the human body. Their polarity establishment starts with axon/dendrite specification. Further compartmentalization occurs during the formation of dendritic spines, which receive most of the excitatory synaptic inputs in the brain. Moreover, not all spines are created equal. Some persist for life, while others are more plastic. This high degree of compartmentalization ensures the input specificity of synaptic transmission and is essential for cognitive functions.

However, it is unclear how neurons can maintain this high level of compartmentalization and achieve both stability and plasticity in spines that are just a few microns apart. Polarity proteins are ideally suited to function in this capacity, as their main job is to compartmentalize the cell by separating and maintaining distinct membrane domains.

A major focus of our lab is to understand the role of a group of polarity regulators called Par (partitioning defective) proteins in dendritic spine morphogenesis and plasticity.  We are also interested in how their regulation of spine plasticity translates to cognitive functions in vivo.  A second direction of the lab is to understand the role of these Par proteins in neurodegenerative diseases such as Alzheimer’s disease.

We employ a wide range of experimental approaches including molecular, biochemical, and live imaging methods such as FRET, FRAP, two-photon in vivo imaging, and optogenetic manipulations of cellular and molecular activities. We use a combination of both primary neuronal cultures and conditional knockout mouse models.

Selected Publications

• Popovitchenko T, Park Y, Page NF, Luo X, Krsnik Z, Liu Y, Salamon I, Stephenson JD, Kraushar ML, Volk NL, Patel SM, Wijeratne HRS, Li D, Suthar KS, Wach A, Sun M, Arnold SJ, Akamatsu W, Okano H, Paillard L, Zhang H, Buyske S, Kostovic I, De Rubeis S, Hart RP, Rasin MR. Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development. Nature Communications. 2020; 11(1), 1674.
• Sun, M., Huang, C., Wang, H. and Zhang, H. Par3 regulates polarized convergence between APP and BACE1 in hippocampal neurons. Neurobiology of Aging, 2019; 77:8793.
• DiBona, V.L., Zhu, W., Shah, M., Rafalia, A., Ben Cheikh, H., Crockett, D.P., and Zhang, H. Loss of Par1b/MARK2 primes microglia during brain development and enhances their sensitivity to injury. Journal of Neuroinflammation, 2019; 16(1):11.
• Winckler, B., Faundez V., Maday, S., Cai, Q. Guimas Almeida, C. and Zhang, H. The endolysosomal system and proteostasis: from development to degeneration. Journal of Neuroscience 2018; 38(44):9364-9374.
• Zhang L.*, Zhang, P.*, Wang G.*, Zhang H.*, Zhang, Y. Yu Y., Zhang M., Xiao, J., Crespo, P., Hell JW, Lin, L., Huganir RL. and Zhu J.J. Ras and Rap signal bidirectional synaptic plasticity via distinct subcellular microdomains. Neuron, 2018; 98:1-18. *Equal contribution.
• Eyo, U.B., Bispo, A., Liu, J., Sabu, S., Wu, R., DiBona, V.L., Zhang, H., Tang, Y. and Wu, L.J. The GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions. Scientific Reports, 2018; 8(1):828.
• Sun, M. and Zhang, H. Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1. Neurobiology of Aging, 2017; 60:129-140.
• Wu, Q., Sun, M., Bernard, L.P. and Zhang, H. Postsynapse Density 95 (PSD-95) serine 561 phosphorylation regulates a conformational switch and bidirectional dendritic spine structural plasticity. Journal of Biological Chemistry, 2017; 292(39) 16150–16160.
• Lim C.S., Wen C., Sheng Y., Wang G., Zhou Z., Wang S., Zhang H., Ye A. and Zhu J.J. Analysis of Ras-BRaf signal transduction with single-molecule force spectroscopy. Small, 2017 doi: 10.1002/smll.201701972.
• Lim, C.S., Kang, X., Mirabella, V., Zhang, H., Bu, Q., Araki, Y., Hoang, E.T., Wang, S., Shen, Y., Choi, S., Kaang, B.S., Chang, Q., Pang, Z.P., Huganir, R.L. and Zhu J.J. BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method. Genes and Development, 2017, 31(6):537552.
• Sun, M., Asghar, S.Z. and Zhang, H. The polarity protein Par3 regulates APP trafficking and processing through the endocytic adaptor protein Numb. Neurobiology of Disease, 2016, Sep;93:1-11. doi: 10.1016/j.nbd.2016.03.022.
• Bernard, L.P. and Zhang, H. MARK/Par1 kinase is activated downstream of NMDA receptors through a PKA-dependent mechanism. PLoS One 2015; 10(5):e0124816. doi: 10.1371 /journal.pone.0124816.
• Yasuda, K., Zhang, H., Loiselle, D. Haystead, T., Macara, I.G. and Mili, S.  The RNAbinding protein Fus directs translation of localized mRNAs in APC-ribonucleoprotein granules. Journal of Cell Biology 2013; 203(5), 737-746.
• Sun, M.*, Bernard, L.P.*, DiBona V.L., Wu, Q. and Zhang, H. Calcium phosphate transfection of primary hippocampal neurons. Journal of Visualized Experiments, 2013; 81, e50808, doi:10.3791/50808. *equal contribution.
• Wu, Q.*, DiBona V.L.*, Bernard, L.P. and Zhang, H.  The polarity protein PAR-1 regulates dendritic spine morphogenesis through phosphorylating PSD-95. Journal of Biological Chemistry 2012; 287(36):30781-30788. *equal contribution.
• Kim, J.-Y. Oh, M.H., Bernard, L.P., Macara, I.G. and Zhang, H. The RhoG/ELMO1/Dock180 signaling module is required for dendritic spine morphogenesis in hippocampal neurons. Journal of Biological Chemistry 2011; 286(43): 37615-24.
• Zhang, H. and Macara, I.G. The PAR-6 polarity protein regulates dendritic spine morphogenesis through p190RhoGAP and the Rho GTPase. Developmental Cell 2008; 14(2): 216-226.
• Zhang, H. and Macara, I.G.  The polarity protein PAR-3 and TIAM1 cooperate in dendritic spine morphogenesis. Nature Cell Biology 2006; 8(3): 227-237.
• Zhang, H., Webb, D.J., Asmussen, H., Niu, S. and Horwitz, A.F.  A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC, Journal of Neuroscience 2005; 25(13):3379-88.
• Zhang, H., Webb, D.J., Asmussen, H. and Horwitz, A.F. Synapse formation is regulated by the signaling adaptor GIT1.  Journal of Cell Biology 2003; 161(1):131-42.

Current Funding

• NIH R01 NS089578: Polarity determinants in synaptic stability and plasticity
• NIH R21 AG063123: Polarity determinants in endolysosomal trafficking and proteostasis
• DOD/ USAMRAA W81XWH-18-1-0388: Targeting novel neurotrophin effectors for treating posttraumatic epilepsy