Trans-omic profiling uncovers molecular controls of early human cerebral organoid formation
Carissa Chen,
Scott Lee,
Katherine G. Zyner,
Milan Fernando,
Victoria Nemeruck,
Emilie Wong,
Lee L. Marshall,
Jesse R. Wark,
Nader Aryamanesh,
Patrick P.L. Tam,
Mark E. Graham,
Anai Gonzalez-Cordero,
Pengyi Yang
Affiliations
Carissa Chen
Computational Systems Biology Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; Embryology Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Scott Lee
Stem Cell and Organoid Facility, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Katherine G. Zyner
Computational Systems Biology Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Milan Fernando
Stem Cell and Organoid Facility, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Victoria Nemeruck
Stem Cell Medicine Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Emilie Wong
Stem Cell Medicine Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Lee L. Marshall
Bioinformatics Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Jesse R. Wark
Synapse Proteomics, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia
Nader Aryamanesh
Bioinformatics Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Patrick P.L. Tam
Embryology Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Mark E. Graham
Synapse Proteomics, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; Corresponding author
Anai Gonzalez-Cordero
Stem Cell and Organoid Facility, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; Stem Cell Medicine Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; Corresponding author
Pengyi Yang
Computational Systems Biology Unit, Children’s Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, School of Mathematics and Statistics, University of Sydney, Sydney, NSW 2006, Australia; Corresponding author
Summary: Defining the molecular networks orchestrating human brain formation is crucial for understanding neurodevelopment and neurological disorders. Challenges in acquiring early brain tissue have incentivized the use of three-dimensional human pluripotent stem cell (hPSC)-derived neural organoids to recapitulate neurodevelopment. To elucidate the molecular programs that drive this highly dynamic process, here, we generate a comprehensive trans-omic map of the phosphoproteome, proteome, and transcriptome of the exit of pluripotency and neural differentiation toward human cerebral organoids (hCOs). These data reveal key phospho-signaling events and their convergence on transcriptional factors to regulate hCO formation. Comparative analysis with developing human and mouse embryos demonstrates the fidelity of our hCOs in modeling embryonic brain development. Finally, we demonstrate that biochemical modulation of AKT signaling can control hCO differentiation. Together, our data provide a comprehensive resource to study molecular controls in human embryonic brain development and provide a guide for the future development of hCO differentiation protocols.
