Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. D., Kulkarni, S., Mudipalli, R., Cui, B., Nishino, S., Grant, G. W., Andersen, J., Sakai, N., Chen, X., Li, M. Maturation and circuit integration of transplanted human cortical organoids.These results highlight the power of this CRISPR-assembloid platform to systematically map NDD genes onto human development and reveal disease mechanisms. LNPK deletion interfered with this endoplasmic reticulum displacement and resulted in abnormal migration. We discovered that, during interneuron migration, the endoplasmic reticulum is displaced along the leading neuronal branch before nuclear translocation. 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. The first screen aimed at interneuron generation revealed 13 candidate genes, including CSDE1 and SMAD4. Here we integrate assembloids with CRISPR screening to investigate the involvement of 425 NDD genes in human interneuron development. We previously developed a platform to study interneuron development and migration in subpallial organoids and forebrain assembloids6. 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. 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. We believe science is a community effort, and accordingly, we have been advancing the field by broadly and openly sharing our technologies with numerous laboratories around the world and organizing the primary research conference and the training courses in the area of cellular models of the human brain. We have carved a unique research program that combines rigorous in vivo and in vitro neuroscience, stem cell and molecular biology approaches to construct and deconstruct previously inaccessible stages of human brain development and function in health and disease. We have actively applied these models in combination with studies in long-term ex vivo brain preparations to acquire a deeper understanding of human physiology, evolution and disease mechanisms. We also pioneered a modular system to integrate 3D brain region-specific organoids and study human neuronal migration and neural circuit formation in functional preparations that we named assembloids. Moreover, when maintained as long-term cultures, they recapitulate an intrinsic program of maturation that progresses towards postnatal stages. We demonstrated that these cultures, such as the ones resembling the cerebral cortex, can be reliably derived across many lines and experiments, contain synaptically connected neurons and non-reactive astrocytes, and can be used to gain mechanistic insights into genetic and environmental brain disorders. We introduced the use of instructive signals for deriving from human pluripotent stem cells self-organizing 3D cellular structures named brain region-specific spheroids/organoids. To address this, we are developing bottom-up approaches to generate and assemble, from multi-cellular components, human neural circuits in vitro and in vivo. Vice Provost for Undergraduate EducationĪ critical challenge in understanding the intricate programs underlying development, assembly and dysfunction of the human brain is the lack of direct access to intact, functioning human brain tissue for detailed investigation by imaging, recording, and stimulation.Office of Vice President for Business Affairs and Chief Financial Officer.Office of VP for University Human Resources.Stanford Woods Institute for the Environment.Stanford Institute for Economic Policy Research (SIEPR).Institute for Stem Cell Biology and Regenerative Medicine.Institute for Human-Centered Artificial Intelligence (HAI).Institute for Computational and Mathematical Engineering (ICME).Freeman Spogli Institute for International Studies.Stanford Doerr School of Sustainability.
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