Xinyu Zhao, PhD

Position title: Professor, Neuroscience, Jenni & Kyle Professor

PhD, University of Washington
Professor, Department of Neuroscience
Jenni & Kyle Professor in Novel Neurodevelopmental Diseases
Director, Rodent Models Sub-Core

Contact Information

Waisman Center
1500 Highland Avenue
Room T513
Madison, WI 53705
608-263-9906
xinyu.zhao@wisc.edu
Zhao Lab

Research Statement

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.

Selected Publications

Guo, Y., & Zhao, X. (2024). CRISPR-based genetic screens in human pluripotent stem cells derived neurons and brain organoids. Cell and tissue research, 10.1007/s00441-024-03934-2. Advance online publication. https://doi.org/10.1007/s00441-024-03934-2
Sirois, C. L., Sandoval, S. O., & Zhao, X. (2024). FMRP gains mitochondrial fission control. Nature cell biology, 10.1038/s41556-024-01567-9. Advance online publication. https://doi.org/10.1038/s41556-024-01567-9
Méndez-Albelo, N. M., Sandoval, S. O., Xu, Z., & Zhao, X. (2024). An in-depth review of the function of RNA-binding protein FXR1 in neurodevelopment. Cell and tissue research, 398(2), 63–77. https://doi.org/10.1007/s00441-024-03912-8
Huang, X., Kumarage, P., Sandoval, S., Zhao, X., & Wang, D. (2024). Protocol for comparative gene expression data analysis between brains and organoids using a cloud-based web app. STAR protocols, 5(4), 103375. Advance online publication. https://doi.org/10.1016/j.xpro.2024.103375
Anshu, K., Kristensen, K., Godar, S. P., Zhou, X., Hartley, S. L., & Litovsky, R. Y. (2024). Speech Recognition and Spatial Hearing in Young Adults With Down Syndrome: Relationships With Hearing Thresholds and Auditory Working Memory. Ear and hearing, 10.1097/AUD.0000000000001549. Advance online publication. https://doi.org/10.1097/AUD.0000000000001549
Yan, Y., Li, X., Gao, Y., Mathivanan, S., Kong, L., Tao, Y., Dong, Y., Li, X., Bhattacharyya, A., Zhao, X., & Zhang, S. C. (2024). 3D bioprinting of human neural tissues with functional connectivity. Cell stem cell, 31(2), 260–274.e7. https://doi.org/10.1016/j.stem.2023.12.009
Shen, M., Sirois, C. L., Guo, Y., Li, M., Dong, Q., Méndez-Albelo, N. M., Gao, Y., Khullar, S., Kissel, L., Sandoval, S. O., Wolkoff, N. E., Huang, S. X., Xu, Z., Bryan, J. E., Contractor, A. M., Korabelnikov, T., Glass, I. A., Doherty, D., Birth Defects Research Laboratory, Levine, J. E., … Zhao, X. (2023). Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development. Neuron, 111(24), 3988–4005.e11. https://doi.org/10.1016/j.neuron.2023.09.014
Scheuer, K. S., Judge, J. M., Zhao, X., & Jackson, M. B. (2023). Velocity of conduction between columns and layers in barrel cortex reported by parvalbumin interneurons. Cerebral cortex (New York, N.Y. : 1991), 33(17), 9917–9926. https://doi.org/10.1093/cercor/bhad254
Rosas, S., Schoeller, K. A., Chang, E., Mei, H., Kats, M. A., Eliceiri, K. W., Zhao, X., & Yesilkoy, F. (2023). Metasurface-Enhanced Mid-Infrared Spectrochemical Imaging of Tissues. Advanced materials (Deerfield Beach, Fla.), 35(28), e2301208. https://doi.org/10.1002/adma.202301208
Guo, Y., Shen, M., Dong, Q., Méndez-Albelo, N. M., Huang, S. X., Sirois, C. L., Le, J., Li, M., Jarzembowski, E. D., Schoeller, K. A., Stockton, M. E., Horner, V. L., Sousa, A. M. M., Gao, Y., Birth Defects Research Laboratory, Levine, J. E., Wang, D., Chang, Q., & Zhao, X. (2023). Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway. Nature communications, 14(1), 3801. https://doi.org/10.1038/s41467-023-39337-0
He, C., Kalafut, N. C., Sandoval, S. O., Risgaard, R., Sirois, C. L., Yang, C., Khullar, S., Suzuki, M., Huang, X., Chang, Q., Zhao, X., Sousa, A. M. M., & Wang, D. (2023). BOMA, a machine-learning framework for comparative gene expression analysis across brains and organoids. Cell reports methods, 3(2), 100409. https://doi.org/10.1016/j.crmeth.2023.100409
Ludwig, A. L., Mayerl, S. J., Gao, Y., Banghart, M., Bacig, C., Fernandez Zepeda, M. A., Zhao, X., & Gamm, D. M. (2023). Re-formation of synaptic connectivity in dissociated human stem cell-derived retinal organoid cultures. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2213418120. https://doi.org/10.1073/pnas.2213418120
Javadi, S., Li, Y., Sheng, J., Zhao, L., Fu, Y., Wang, D., & Zhao, X. (2022). Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of fragile X syndrome. BMC medicine, 20(1), 163. https://doi.org/10.1186/s12916-022-02370-9
Kristensen, K., Lorenz, K. M., Zhou, X., Piro-Gambetti, B., Hartley, S. L., Godar, S. P., Diel, S., Neubauer, E., & Litovsky, R. Y. (2022). Language and executive functioning in young adults with Down syndrome. Journal of intellectual disability research: JIDR, 66(1-2), 151–161. DOI: 10.1111/jir.12868
Zhou, X., Planalp, E. M., Heinrich, L., Pletcher, C., DiPiero, M., Alexander, A. L., Litovsky, R. Y., & Dean, D. C., 3rd (2022). Inhibitory Control in Children 4-10 Years of Age: Evidence From Functional Near-Infrared Spectroscopy Task-Based Observations. Frontiers in human neuroscience, 15, 798358. DOI: 10.3389/fnhum.2021.798358
Hunt, J., Li, M., Risgaard, R., Ananiev, G. E., Wildman, S., Zhang, F., Bugni, T. S., Zhao, X., & Bhattacharyya, A. (2021). High Throughput Small Molecule Screen for Reactivation of FMR1 in Fragile X Syndrome Human Neural Cells. Cells, 11(1), 69. https://doi.org/10.3390/cells11010069
Shen, M., Guo, Y., Dong, Q., Gao, Y., Stockton, M. E., Li, M., Kannan, S., Korabelnikov, T., Schoeller, K. A., Sirois, C. L., Zhou, C., Le, J., Wang, D., Chang, Q., Sun, Q. Q., & Zhao, X. (2021). FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors. Molecular psychiatry, 26(11), 6845–6867. https://doi.org/10.1038/s41380-021-01096-z
Gao, Y., & Zhao, X. (2020). sncRiboTag-Seq: cell-type-specific RiboTag-Seq for cells in low abundance in mouse brain tissue. STAR protocols, 2(1), 100231. https://doi.org/10.1016/j.xpro.2020.100231
Men, Y., Ye, L., Risgaard, R. D., Promes, V., Zhao, X., Paukert, M., & Yang, Y. (2020). Astroglial FMRP deficiency cell-autonomously up-regulates miR-128 and disrupts developmental astroglial mGluR5 signaling. Proceedings of the National Academy of Sciences of the United States of America, 117(40), 25092–25103. https://doi.org/10.1073/pnas.2014080117
Zhao, X., & van Praag, H. (2020). Steps towards standardized quantification of adult neurogenesis. Nature communications, 11(1), 4275. https://doi.org/10.1038/s41467-020-18046-y
Gao Y, Shen M, Gonzalez JC, Dong Q, Kannan S, Hoang JT, Eisinger BE, Pandey J, Javadi S, Chang Q, Wang D, Overstreet-Wadiche L, Zhao X. (2020). RGS6 Mediates Effects of Voluntary Running on Adult Hippocampal Neurogenesis. Cell Reports, 32(5):107997. doi: 10.1016/j.celrep.2020.107997.
Zhao, X., & Bhattacharyya, A. (2020). Advances in Human Stem Cells and Genome Editing to Understand and Develop Treatment for Fragile X Syndrome. Advances in neurobiology, 25, 33–53. https://doi.org/10.1007/978-3-030-45493-7_2
Li M, Shin J, Risgaard RD, Parries MJ, Wang J, Chasman D, Liu S, Roy S, Bhattacharyya A, Zhao X. (2020). Identification of FMR1-regulated molecular networks in human neurodevelopment. Genome Research, 30(3):361-374. doi: 10.1101/gr.251405.119. Epub 2020 Mar 16. PMID: 32179589; PMCID: PMC7111522.
Li Y, Shen M, Stockton ME, Zhao X. (2019). Hippocampal deficits in neurodevelopmental disorders. Neurobiology of Learning and Memory, 165:106945. doi: 10.1016/j.nlm.2018.10.001.
Li, M., Hunt, J., Bhattacharyya, A., & Zhao, X. (2019). One-Step Generation of Seamless Luciferase Gene Knockin Using CRISPR/Cas9 Genome Editing in Human Pluripotent Stem Cells. Methods in molecular biology (Clifton, N.J.), 1942, 61–69. https://doi.org/10.1007/978-1-4939-9080-1_5
Hunt, J., Li, M., Zhao, X., & Bhattacharyya, A. (2019). Using Human Neural Progenitor Cell Models to Conduct Large-Scale Drug Screens for Neurological and Psychiatric Diseases. Methods in molecular biology (Clifton, N.J.), 1942, 79–88. https://doi.org/10.1007/978-1-4939-9080-1_7
Shen M, Wang F, Li M, Sah N, Stockton ME, Tidei JJ, Gao Y, Korabelnikov T, Kannan S, Vevea JD, Chapman ER, Bhattacharyya A, van Praag H, Zhao X. (2019). Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in FMR1-mutant mice. Nature Neuroscience, 22(3):386-400. doi: 10.1038/s41593-019-0338-y.
Sun J, Carlson-Stevermer J, Das U, Shen M, Delenclos M, Snead AM, Koo SY, Wang L, Qiao D, Loi J, Petersen AJ, Stockton M, Bhattacharyya A, Jones MV, Zhao X, McLean PJ, Sproul AA, Saha K, Roy S. (2019). CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nature Communications, 3;10(1):53. doi: 10.1038/s41467-018-07971-8.
Sun Y, Gao Y, Tidei JJ, Shen M, Hoang JT, Wagner DF, Zhao X. (2019). Loss of MeCP2 in immature neurons leads to impaired network integration. Human Molecular Genetics, 15;28(2):245-257. doi: 10.1093/hmg/ddy338.
Moon HY, Javadi S, Stremlau M, Yoon KJ, Becker B, Kang SU, Zhao X, van Praag H. (2019). Conditioned media from AICAR-treated skeletal muscle cells increases neuronal differentiation of adult neural progenitor cells. Neuropharmacology, 145(Pt A):123-130. doi: 10.1016/j.neuropharm.2018.10.041.
Zhao X, Bhattacharyya A. (2018). Human Models Are Needed for Studying Human Neurodevelopmental Disorders. American Journal of Human Genetics, 103(6):829-857. doi: 10.1016/j.ajhg.2018.10.009. Review.
Eisinger BE, Zhao X. (2018). Identifying molecular mediators of environmentally enhanced neurogenesis. Cell and Tissue Research. 371(1):7-21. doi: 10.1007/s00441-017-2718-5.
Zhao X, Moore DL. (2018). Neural stem cells: developmental mechanisms and disease modeling. Cell and Tissue Research. 371(1):1-6. doi: 10.1007/s00441-017-2738-1.
Bayguinov PO, Ma Y, Gao Y, Zhao X, Jackson MB. (2017). Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor. Journal of Neuroscience, 37(38):9305-9319. doi: 10.1523/JNEUROSCI.1363-17.2017.
Zhang P, Rausch C, Hastert FD, Boneva B, Filatova A, Patil SJ, Nuber UA, Gao Y, Zhao X, Cardoso MC. (2017). Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner. Nucleic Acids Research, 45(12):7118-7136. doi: 10.1093/nar/gkx281.
Patzlaff NE, Nemec KM, Malone SG, Li Y, Zhao X. (2017). Fragile X related protein 1 (FXR1P) regulates proliferation of adult neural stem cells. Human Molecular Genetics, 26(7):1340-1352. doi: 10.1093/hmg/ddx034.
Gao Y, Wang F, Eisinger BE, Kelnhofer LE, Jobe EM, Zhao X. (2017). Integrative Single-Cell Transcriptomics Reveals Molecular Networks Defining Neuronal Maturation During Postnatal Neurogenesis. Cerebral Cortex, 27(3):2064-2077. doi: 10.1093/cercor/bhw040.
Jobe EM, Gao Y, Eisinger BE, Mladucky JK, Giuliani CC, Kelnhofer LE, Zhao X. (2017). Methyl-CpG-Binding Protein MBD1 Regulates Neuronal Lineage Commitment through Maintaining Adult Neural Stem Cell Identity. Journal of Neuroscience. 37(3):523-536. doi: 10.1523/JNEUROSCI.1075-16.2016.
Li M, Zhao H, Ananiev GE, Musser MT, Ness KH, Maglaque DL, Saha K, Bhattacharyya A, Zhao X. (2017). Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells. Stem Cells, 35(1):158-169. doi: 10.1002/stem.2463.
Hsieh J, Zhao X. (2016). Genetics and Epigenetics in Adult Neurogenesis. Cold Spring Harbor Perspectives in Biology. 8(6). pii: a018911. doi: 10.1101/cshperspect.a018911.
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.
Bhattacharyya A, Zhao X. (2016) 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, 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.
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.
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, 112(36):E4995-5004. doi: 10.1073/pnas.1513780112.
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, 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, 11(10):1651-66. doi: 10.1016/j.celrep.2015.05.013.
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.
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.
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, 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.