Professional Education

  • Bachelor of Medicine, Peking University (2011)
  • Doctor of Philosophy, Unlisted School (2018)
  • Doctor of philosophy, Baylor College of Medicine, Neuroscience (2018)

Stanford Advisors

Lab Affiliations

All Publications

  • Antisense oligonucleotide therapeutic approach for Timothy syndrome. Nature Chen, X., Birey, F., Li, M. Y., Revah, O., Levy, R., Thete, M. V., Reis, N., Kaganovsky, K., Onesto, M., Sakai, N., Hudacova, Z., Hao, J., Meng, X., Nishino, S., Huguenard, J., Pașca, S. P. 2024; 628 (8009): 818-825


    Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

    View details for DOI 10.1038/s41586-024-07310-6

    View details for PubMedID 38658687

    View details for PubMedCentralID 1149428

  • A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels. Genes & development Zhou, J., Cattoglio, C., Shao, Y., Tirumala, H. P., Vetralla, C., Bajikar, S. S., Li, Y., Chen, H., Wang, Q., Wu, Z., Tang, B., Zahabiyon, M., Bajic, A., Meng, X., Ferrie, J. J., LaGrone, A., Zhang, P., Kim, J. J., Tang, J., Liu, Z., Darzacq, X., Heintz, N., Tjian, R., Zoghbi, H. Y. 2023


    Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases.

    View details for DOI 10.1101/gad.350733.123

    View details for PubMedID 37890975

  • Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment NATURE Meng, X., Yao, D., Imaizumi, K., Chen, X., Kelley, K. W., Reis, N., Thete, M., Arjun McKinney, A., Kulkarni, S., Panagiotakos, G., Bassik, M. C., Pasca, S. P. 2023
  • Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment. Nature Meng, X., Yao, D., Imaizumi, K., Chen, X., Kelley, K. W., Reis, N., Thete, M. V., Arjun McKinney, A., Kulkarni, S., Panagiotakos, G., Bassik, M. C., Pașca, S. P. 2023


    The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain1-3, which has been challenging to study at inaccessible stages of late gestation and early postnatal human development4. Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development5, but which of these NDD genes affect interneuron generation and migration, and how they mediate these effects remains unknown. We previously developed a platform to study interneuron development and migration in subpallial organoids and forebrain assembloids6. Here we integrate assembloids with CRISPR screening to investigate the involvement of 425 NDD genes in human interneuron development. The first screen aimed at interneuron generation revealed 13 candidate genes, including CSDE1 and SMAD4. We subsequently conducted an interneuron migration screen in more than 1,000 forebrain assembloids that identified 33 candidate genes, including cytoskeleton-related genes and the endoplasmic reticulum-related gene LNPK. We discovered that, during interneuron migration, the endoplasmic reticulum is displaced along the leading neuronal branch before nuclear translocation. LNPK deletion interfered with this endoplasmic reticulum displacement and resulted in abnormal migration. These results highlight the power of this CRISPR-assembloid platform to systematically map NDD genes onto human development and reveal disease mechanisms.

    View details for DOI 10.1038/s41586-023-06564-w

    View details for PubMedID 37758944

    View details for PubMedCentralID 4349583

  • The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Science translational medicine Pluvinage, J. V., Sun, J., Claes, C., Flynn, R. A., Haney, M. S., Iram, T., Meng, X., Lindemann, R., Riley, N. M., Danhash, E., Chadarevian, J. P., Tapp, E., Gate, D., Kondapavulur, S., Cobos, I., Chetty, S., Pașca, A. M., Pașca, S. P., Berry-Kravis, E., Bertozzi, C. R., Blurton-Jones, M., Wyss-Coray, T. 2021; 13 (622): eabg2919


    [Figure: see text].

    View details for DOI 10.1126/scitranslmed.abg2919

    View details for PubMedID 34851695

  • Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia. Frontiers in neurology Ward, C. S., Huang, T. W., Herrera, J. A., Samaco, R. C., McGraw, C. M., Parra, D. E., Arvide, E. M., Ito-Ishida, A., Meng, X., Ure, K., Zoghbi, H. Y., Neul, J. L. 2020; 11: 593554


    Rett Syndrome (RTT) is a neurodevelopmental disorder caused by loss of function of the transcriptional regulator Methyl-CpG-Binding Protein 2 (MeCP2). In addition to the characteristic loss of hand function and spoken language after the first year of life, people with RTT also have a variety of physiological and autonomic abnormalities including disrupted breathing rhythms characterized by bouts of hyperventilation and an increased frequency of apnea. These breathing abnormalities, that likely involve alterations in both the circuitry underlying respiratory pace making and those underlying breathing response to environmental stimuli, may underlie the sudden unexpected death seen in a significant fraction of people with RTT. In fact, mice lacking MeCP2 function exhibit abnormal breathing rate response to acute hypoxia and maintain a persistently elevated breathing rate rather than showing typical hypoxic ventilatory decline that can be observed among their wild-type littermates. Using genetic and pharmacological tools to better understand the course of this abnormal hypoxic breathing rate response and the neurons driving it, we learned that the abnormal hypoxic breathing response is acquired as the animals mature, and that MeCP2 function is required within excitatory, inhibitory, and modulatory populations for a normal hypoxic breathing rate response. Furthermore, mice lacking MeCP2 exhibit decreased hypoxia-induced neuronal activity within the nucleus tractus solitarius of the dorsal medulla. Overall, these data provide insight into the neurons driving the circuit dysfunction that leads to breathing abnormalities upon loss of MeCP2. The discovery that combined dysfunction across multiple neuronal populations contributes to breathing dysfunction may provide insight into sudden unexpected death in RTT.

    View details for DOI 10.3389/fneur.2020.593554

    View details for PubMedID 33193060

    View details for PubMedCentralID PMC7662121

  • Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions. eLife Meng, X., McGraw, C. M., Wang, W., Jing, J., Yeh, S. Y., Wang, L., Lopez, J., Brown, A. M., Lin, T., Chen, W., Xue, M., Sillitoe, R. V., Jiang, X., Zoghbi, H. Y. 2019; 8


    Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of Neurexophilin4 caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with α-neurexin and GABAARs in the cerebellum. Loss of Neurexophilin4 impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the Neurexophilin4 null mice. Our data illustrate how selectively expressed Neurexophilin4, an α-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.

    View details for DOI 10.7554/eLife.46773

    View details for PubMedID 31524598

  • Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders. eLife Meng, X., Wang, W., Lu, H., He, L. J., Chen, W., Chao, E. S., Fiorotto, M. L., Tang, B., Herrera, J. A., Seymour, M. L., Neul, J. L., Pereira, F. A., Tang, J., Xue, M., Zoghbi, H. Y. 2016; 5


    Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

    View details for DOI 10.7554/eLife.14199

    View details for PubMedID 27328325

    View details for PubMedCentralID PMC4946906

  • Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model. Neuron Lu, H. n., Ash, R. T., He, L. n., Kee, S. E., Wang, W. n., Yu, D. n., Hao, S. n., Meng, X. n., Ure, K. n., Ito-Ishida, A. n., Tang, B. n., Sun, Y. n., Ji, D. n., Tang, J. n., Arenkiel, B. R., Smirnakis, S. M., Zoghbi, H. Y. 2016; 91 (4): 739–47


    Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice.

    View details for DOI 10.1016/j.neuron.2016.07.018

    View details for PubMedID 27499081

    View details for PubMedCentralID PMC5019177