PhD, University of Washington
Professor, Department of Neuroscience
Jenni & Kyle Professor
Waisman Center Investigator
The research in our laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neurodevelopment with the goal of applying this knowledge in the treatment of neurological disorders and injuries.
Stem cells have two fundamental properties: self-renewal and multipotency. During development, stem cells and resulting progenitor cells are responsible for generating all the tissues and cells of an organism. In the adult, stem cells exist in many tissues throughout life and may play critical roles in physiological functions and tissue regeneration. The maintenance of their "stemness" state and commitment to differentiation are tightly controlled by both intrinsic genetic and epigenetic programs and extrinsic stimuli.
Neural stem cells in the postnatal brain have significant roles in both normal brain functions, such as learning and memory and the brain's response to injuries. My laboratory is investigating the mechanisms governing the behaviors and functions of neural stem cells in both healthy conditions and in neurological diseases.
Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and noncoding RNAs have profound regulatory roles in controlling mammalian gene expression. Disturbance of these interacting systems can lead to inappropriate expression or silencing of genes, causing an array of multi-system disorders. A main focus of my lab research is to understand the epigenetic basis of cell fate specification and neurodevelopment.
Neurodevelopmental disorders are highly heterogeneous constellation of disorders, both in terms of etiology and clinical manifestations. Using neural stem cells as model systems, we are investigating the molecular mechanisms that regulate neuronal development during postnatal period and their implications in human neurodevelopmental disorders such as Rett Syndrome, Autism, and Fragile X syndrome.
Li R, Dong Q, Yuan X, Zeng X, Gao Y, Chiao C, Li H, Zhao X, Keles S, Wang Z, Chang Q. (2016) Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome. PLoS Genetics. 28;12(6):e1006129. doi: 10.1371/journal.pgen.
Li Y, Stockton ME, Bhuiyan I, Eisinger BE, Gao Y, Miller JL, Bhattacharyya A, Zhao X. (2016) MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Science Translational Medicine. 27;8(336):336ra61. doi: 10.1126/scitranslmed.aad9370.
Chow CL, Guo W, Trivedi P, Zhao X, Gubbels SP. (2015) Characterization of a unique cell population marked by transgene expression in the adult cochlea of nestin-CreER T2 /tdTomato-reporter mice. Journal of Comparative Neurology. 1;523(10):1474-87. doi: 10.1002/cne.23747.
Guo W, Polich ED, Su J, Gao Y, Christopher DM, Allan AM, Wang M, Wang F, Wang G, Zhao X. (2015) Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms. Cell Reports. 16;11(10):1651-66. doi: 10.1016/j.celrep.2015.05.013.
Wang F, Tidei JJ, Polich ED, Gao Y, Zhao H, Perrone-Bizzozero NI, Guo W, Zhao X. (2015) Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis. Proceedings of the National Academy of Sciences USA. 8;112(36):E4995-5004. doi: 10.1073/pnas.1513780112.
Gao Y, Su J, Guo W, Polich ED, Magyar DP, Xing Y, Li H, Smrt RD, Chang Q, Zhao X. (2015) Inhibition of miR-15a Promotes BDNF Expression and Rescues Dendritic Maturation Deficits in MeCP2-Deficient Neurons. Stem Cells. 33(5):1618-29. doi: 10.1002/stem.1950.
Bhattacharyya A, Zhao X. (2015) Human pluripotent stem cell models of Fragile X syndrome. Molecular and Cellular Neurosciences. 73:43-51. PubMed PMID: 26640241; PubMed Central PMCID: PMC4867245.
Li Y, Zhao X. (2014) Concise review: Fragile X proteins in stem cell maintenance and differentiation. Stem Cells. 32(7):1724-33.
Li H, Zhong X, Chau KF, Santistevan NJ, Guo W, Kong G, Li X, Kadakia M, Masliah J, Chi J, Jin P, Zhang J, Zhao X, Chang Q. (2014) Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signaling pathway. Nature Communications. 25;5:5601.
Guo W, Tsujimura K, Otsuka I M, Irie K, Igarashi K, Nakashima K, Zhao X. (2014) VPA alleviates neurological deficits and restores gene expression in a mouse model of Rett syndrome. PLoS One. 9(6):e100215.
Guo W, Murthy AC, Zhang L, Johnson EB, Schaller EG, Allan AM, Zhao X. (2012) Inhibition of GSK3β improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome. Human Moleculer Genetics. 21(3):681-91.
Jobe EM, McQuate AL, Zhao X. (2012) Crosstalk among Epigenetic Pathways Regulates Neurogenesis. Frontiers in Neuroscience. 6:59.
Guo W, Patzlaff NE, Jobe EM, Zhao X. (2012) Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. Nature Protocols. 7(11):2005-12.
Smrt RD, Pfeiffer RL, Zhao X. (2011) Age-dependent expression of MeCP2 in a heterozygous mosaic mouse model. Human Molecular Genetics . May 1;20(9):1834-43 PMCID: PMC3071674.
Guo W, Allan AM, Zong R, Zhang L, Johnson EB, Schaller EG, Murthy AC, Goggin SL, Eisch AJ, Oostra BA, Nelson DL, Jin P, Zhao X. (2011) Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nature Medicine. May;17(5):559-65 PMCID: PMC3140952.
Liu C, Teng ZQ, Santistevan NJ, Szulwach KE, Guo W, Jin P, Zhao X. (2010) Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. May 7;6(5):433-44 PMCID: PMC2867837.
Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, Teng ZQ, Luo Y, Peng J, Bordey A, Jin P, Zhao X. (2010) MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells. Jun;28(6):1060-70 PMCID: PMC3140955.
Luo Y, Shan G, Guo W, Smrt RD, Johnson EB, Li X, Pfeiffer RL, Szulwach KE, Duan R, Barkho BZ, Li W, Liu C, Jin P, Zhao X. (2010) Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genetics. Apr 8;6(4):e1000898.