Minyin Li

All Publications

• Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nature medicine Khan, T. A., Revah, O., Gordon, A., Yoon, S. J., Krawisz, A. K., Goold, C., Sun, Y., Kim, C. H., Tian, Y., Li, M. Y., Schaepe, J. M., Ikeda, K., Amin, N. D., Sakai, N., Yazawa, M., Kushan, L., Nishino, S., Porteus, M. H., Rapoport, J. L., Bernstein, J. A., O'Hara, R., Bearden, C. E., Hallmayer, J. F., Huguenard, J. R., Geschwind, D. H., Dolmetsch, R. E., Paşca, S. P. 2020

  Abstract

  22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.

  View details for DOI 10.1038/s41591-020-1043-9

  View details for PubMedID 32989314

• Retinoid X Receptor α Regulates DHA-Dependent Spinogenesis and Functional Synapse Formation In Vivo. Cell reports Cao, H., Li, M. Y., Li, G., Li, S. J., Wen, B., Lu, Y., Yu, X. 2020; 31 (7): 107649

  Abstract

  Coordinated intracellular and extracellular signaling is critical to synapse development and functional neural circuit wiring. Here, we report that unesterified docosahexaenoic acid (DHA) regulates functional synapse formation in vivo via retinoid X receptor α (Rxra) signaling. Using Rxra conditional knockout (cKO) mice and virus-mediated transient gene expression, we show that endogenous Rxra plays important roles in regulating spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. We further show that the effects of RXRA are mediated through its DNA-binding domain in a cell-autonomous and reversible manner. Moreover, unesterified DHA increases spine formation and excitatory synaptic transmission in vivo in an Rxra-dependent fashion. Rxra cKO mice generally behave normally but show deficits in behavior tasks associated with social memory. Together, these results demonstrate that unesterified DHA signals through RXRA to regulate spinogenesis and functional synapse formation, providing insight into the mechanism through which DHA promotes brain development and cognitive function.

  View details for DOI 10.1016/j.celrep.2020.107649

  View details for PubMedID 32433958

• Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells. Nature biotechnology Miura, Y., Li, M. Y., Birey, F., Ikeda, K., Revah, O., Thete, M. V., Park, J. Y., Puno, A., Lee, S. H., Porteus, M. H., Pașca, S. P. 2020; 38 (12): 1421–30

  Abstract

  Cortico-striatal projections are critical components of forebrain circuitry that regulate motivated behaviors. To enable the study of the human cortico-striatal pathway and how its dysfunction leads to neuropsychiatric disease, we developed a method to convert human pluripotent stem cells into region-specific brain organoids that resemble the developing human striatum and include electrically active medium spiny neurons. We then assembled these organoids with cerebral cortical organoids in three-dimensional cultures to form cortico-striatal assembloids. Using viral tracing and functional assays in intact or sliced assembloids, we show that cortical neurons send axonal projections into striatal organoids and form synaptic connections. Medium spiny neurons mature electrophysiologically following assembly and display calcium activity after optogenetic stimulation of cortical neurons. Moreover, we derive cortico-striatal assembloids from patients with a neurodevelopmental disorder caused by a deletion on chromosome 22q13.3 and capture disease-associated defects in calcium activity, showing that this approach will allow investigation of the development and functional assembly of cortico-striatal connectivity using patient-derived cells.

  View details for DOI 10.1038/s41587-020-00763-w

  View details for PubMedID 33273741

• A Critical Role of Presynaptic Cadherin/Catenin/p140Cap Complexes in Stabilizing Spines and Functional Synapses in the Neocortex. Neuron Li, M. Y., Miao, W. Y., Wu, Q. Z., He, S. J., Yan, G., Yang, Y., Liu, J. J., Taketo, M. M., Yu, X. 2017; 94 (6): 1155–72.e8

  Abstract

  The formation of functional synapses requires coordinated assembly of presynaptic transmitter release machinery and postsynaptic trafficking of functional receptors and scaffolds. Here, we demonstrate a critical role of presynaptic cadherin/catenin cell adhesion complexes in stabilizing functional synapses and spines in the developing neocortex. Importantly, presynaptic expression of stabilized β-catenin in either layer (L) 4 excitatory neurons or L2/3 pyramidal neurons significantly upregulated excitatory synaptic transmission and dendritic spine density in L2/3 pyramidal neurons, while its sparse postsynaptic expression in L2/3 neurons had no such effects. In addition, presynaptic β-catenin expression enhanced release probability of glutamatergic synapses. Newly identified β-catenin-interacting protein p140Cap is required in the presynaptic locus for mediating these effects. Together, our results demonstrate that cadherin/catenin complexes stabilize functional synapses and spines through anterograde signaling in the neocortex and provide important molecular evidence for a driving role of presynaptic components in spinogenesis in the neocortex.

  View details for DOI 10.1016/j.neuron.2017.05.022

  View details for PubMedID 28641114

• CRISPR-Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development. Cell research Wang, L., Li, M. Y., Qu, C., Miao, W. Y., Yin, Q., Liao, J., Cao, H. T., Huang, M., Wang, K., Zuo, E., Peng, G., Zhang, S. X., Chen, G., Li, Q., Tang, K., Yu, Q., Li, Z., Wong, C. C., Xu, G., Jing, N., Yu, X., Li, J. 2017; 27 (6): 815–29

  Abstract

  Studying the early function of essential genes is an important and challenging problem in developmental biology. Here, we established a method for rapidly inducing CRISPR-Cas9-mediated mutations in one blastomere of two-cell stage embryos, termed 2-cell embryo-CRISPR-Cas9 injection (2CC), to study the in vivo function of essential (or unknown) genes in founder chimeric mice. By injecting both Cre mRNA and CRISPR-Cas9 targeting the gene of interest into fluorescent reporter mice, the 2CC method can trace both wild-type and mutant cells at different developmental stages, offering internal control for phenotypic analyses of mutant cells. Using this method, we identified novel functions of the essential gene Tet3 in regulating excitatory and inhibitory synaptic transmission in the developing mouse cerebral cortex. By generating chimeric mutant mice, the 2CC method allows for the rapid screening of gene function in multiple tissues and cell types in founder chimeric mice, significantly expanding the current armamentarium of genetic tools.

  View details for DOI 10.1038/cr.2017.58

  View details for PubMedID 28429771

  View details for PubMedCentralID PMC5518876

• Postsynaptic spiking homeostatically induces cell-autonomous regulation of inhibitory inputs via retrograde signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience Peng, Y. R., Zeng, S. Y., Song, H. L., Li, M. Y., Yamada, M. K., Yu, X. 2010; 30 (48): 16220–31

  Abstract

  Developing neural circuits face the dual challenge of growing in an activity-induced fashion and maintaining stability through homeostatic mechanisms. Compared to our understanding of homeostatic regulation of excitatory synapses, relatively little is known about the mechanism mediating homeostatic plasticity of inhibitory synapses, especially that following activity elevation. Here, we found that elevating neuronal activity in cultured hippocampal neurons for 4 h significantly increased the frequency and amplitude of mIPSCs, before detectable change at excitatory synapses. Consistently, we observed increases in presynaptic and postsynaptic proteins of GABAergic synapses, including GAD65, vGAT, and GABA(A)Rα1. By suppressing activity-induced increase of neuronal firing with expression of the inward rectifier potassium channel Kir2.1 in individual neurons, we showed that elevation in postsynaptic spiking activity is required for activity-dependent increase in the frequency and amplitude of mIPSCs. Importantly, directly elevating spiking in individual postsynaptic neurons, by capsaicin activation of overexpressed TRPV1 channels, was sufficient to induce increased mIPSC amplitude and frequency, mimicking the effect of elevated neuronal activity. Downregulating BDNF expression in the postsynaptic neuron or its extracellular scavenging prevented activity-induced increase in mIPSC frequency, consistent with a role of BDNF-dependent retrograde signaling in this process. Finally, elevating activity in vivo by kainate injection increased both mIPSC amplitude and frequency in CA1 pyramidal neurons. Thus, spiking-induced, cell-autonomous upregulation of GABAergic synaptic inputs, through retrograde BDNF signaling, represents an early adaptive response of neural circuits to elevated network activity.

  View details for DOI 10.1523/JNEUROSCI.3085-10.2010

  View details for PubMedID 21123568