The overarching goal of this program is to define cellular and molecular events during neural development vulnerable to genetic perturbations that increase risk for neurodevelopmental and neurological disorders. Currently, our knowledge of human brain development is largely inferred from animal models, indirect measures of human development, and limited access to human neural tissue. All of these are valid tools to piece together the sequential processes of human neural development but are not sufficient to describe the dynamics with enough temporal or molecular resolution to understand mechanistically how genetic risk factors can affect brain formation and function. Technological advances in cellular reprogramming have now made it possible to derive induced pluripotent stem cells (iPSCs) from adult patients, which are a renewable resource for the generation of human neurons with disease-relevant genetic features. This long-term research program is designed to incorporate human iPSC-based studies with animal models to provide a comprehensive and longitudinal understanding of neural development, from neural stem cell behavior to neuronal development, synapse formation and circuit integration. As a proof-of-principle, these studies will use a prominent copy number variation (CNV) risk factor for multiple neurological disorders, 15q11.2CNVs, to illustrate how multifaceted interrogations of the basic biology of neural development in the context of genetic variation can reveal new targets for testing mechanism-based intervention in relevant subtypes of human neurons, as well as animal models of neural function and behavior. Building on significant scientific discoveries we have made in the fields of stem cell biology, adult neurogenesis, and patient-specific iPSCs, and technological innovations we have developed to meet critical challenges in each of these fields, our primary research focus is to integrate multiple levels of analysis to provide a high-resolution description of the cellular processes and molecular mechanisms of neural development that can be used to probe genetic or environmental risk for neurological disorders. Three interlinked projects will be pursued. Project 1 will focus on adult mouse neurogenesis as a model for neural development and use clonal analysis of neural stem cells and their development, single-cell transcriptome analysis, and transgenic mouse models to dissect molecular, cellular, and circuit level effects of genetic mutations on neural development; Project 2 will use human iPSCs with known genetic risk factors, and targeted differentiation protocols, to interrogate human neural development in 2D and 3D cultures; and Project 3 will focus on identifying the molecular mechanisms and targets of risk genes in both animal models and human iPSC-derived neurons and the rescue of observed deficits through rational therapeutic intervention. This is an opportune moment to synthesize recently developed technologies and build a novel translational platform to study underlying mechanisms of neurological disorders, and facilitate the identification of strategies to diagnose, treat, and prevent the often debilitating consequences of dysregulated neural development.
Understanding the biological role and underlying mechanisms of genetic risk factors in neural development will allow for more targeted therapeutic interventions for neurodevelopmental and neurological disorders. Combining animal models with novel human stem cell culture systems provides a new platform for the study of fundamental processes of human brain development and rational intervention.
|Yang, Shu; Xu, Miao; Lee, Emily M et al. (2018) Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry. Cell Discov 4:31|
|Wang, Xinyuan; Christian, Kimberly M; Song, Hongjun et al. (2018) Synaptic dysfunction in complex psychiatric disorders: from genetics to mechanisms. Genome Med 10:9|
|Berg, Daniel A; Bond, Allison M; Ming, Guo-Li et al. (2018) Radial glial cells in the adult dentate gyrus: what are they and where do they come from? F1000Res 7:277|
|Song, Guang; Rho, Hee-Sool; Pan, Jianbo et al. (2018) Multiplexed Biomarker Panels Discriminate Zika and Dengue Virus Infection in Humans. Mol Cell Proteomics 17:349-356|
|Yoon, Ki-Jun; Ming, Guo-Li; Song, Hongjun (2018) Epitranscriptomes in the Adult Mammalian Brain: Dynamic Changes Regulate Behavior. Neuron 99:243-245|
|Yoon, Ki-Jun; Vissers, Caroline; Ming, Guo-Li et al. (2018) Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence. J Cell Biol 217:1901-1914|
|Shi, Hailing; Zhang, Xuliang; Weng, Yi-Lan et al. (2018) m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563:249-253|
|Qian, Xuyu; Jacob, Fadi; Song, Mingxi Max et al. (2018) Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc 13:565-580|
|Weng, Yi-Lan; Wang, Xu; An, Ran et al. (2018) Epitranscriptomic m6A Regulation of Axon Regeneration in the Adult Mammalian Nervous System. Neuron 97:313-325.e6|
|Christian, Kimberly M; Song, Hongjun; Ming, Guo-Li (2018) A previously undetected pathology of Zika virus infection. Nat Med 24:258-259|
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