Single-Cell Analysis of Human Retina Identifies Evolutionarily Conserved and Species-Specific Mechanisms Controlling Development.
Yufeng Lu, Fion Shiau, Wenyang Yi, Suying Lu, Qian Wu, Joel D Pearson, Alyssa Kallman, Suijuan Zhong, Thanh Hoang, Zhentao Zuo, Fangqi Zhao, Mei Zhang, Nicole Tsai, Yan Zhuo, Sheng He, Jun Zhang, Genevieve L Stein-O'Brien, Thomas D Sherman, Xin Duan, Elana J Fertig, Loyal A Goff, Donald J Zack, James T Handa, Tian Xue, Rod Bremner, Seth Blackshaw, Xiaoqun Wang, Brian S Clark
Author Information
Yufeng Lu: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Fion Shiau: John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Wenyang Yi: Hefei National Laboratory for Physical Sciences, at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
Suying Lu: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health Systems, Department of Ophthalmology and Vision Science, and Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1X5, Canada.
Qian Wu: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
Joel D Pearson: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health Systems, Department of Ophthalmology and Vision Science, and Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1X5, Canada.
Alyssa Kallman: Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Suijuan Zhong: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Thanh Hoang: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zhentao Zuo: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Fangqi Zhao: Obstetrics and Gynecology Medical Center of Severe Cardiovascular of Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Mei Zhang: Hefei National Laboratory for Physical Sciences, at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
Nicole Tsai: Departments of Ophthalmology and Physiology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Yan Zhuo: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Sheng He: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Jun Zhang: Obstetrics and Gynecology Medical Center of Severe Cardiovascular of Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Genevieve L Stein-O'Brien: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Thomas D Sherman: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Xin Duan: Departments of Ophthalmology and Physiology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Elana J Fertig: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Data Intensive Engineering and Science, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Computational Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Mathematical Institute for Data Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Loyal A Goff: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
Donald J Zack: Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
James T Handa: Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Tian Xue: Hefei National Laboratory for Physical Sciences, at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: xuetian@ustc.edu.cn.
Rod Bremner: Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health Systems, Department of Ophthalmology and Vision Science, and Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address: bremner@lunenfeld.ca.
Seth Blackshaw: Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: sblack@jhmi.edu.
Xiaoqun Wang: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Brain Disorders, Beijing 100069, China. Electronic address: xiaoqunwang@ibp.ac.cn.
Brian S Clark: John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: brian.s.clark@wustl.edu.
The development of single-cell RNA sequencing (scRNA-seq) has allowed high-resolution analysis of cell-type diversity and transcriptional networks controlling cell-fate specification. To identify the transcriptional networks governing human retinal development, we performed scRNA-seq analysis on 16 time points from developing retina as well as four early stages of retinal organoid differentiation. We identified evolutionarily conserved patterns of gene expression during retinal progenitor maturation and specification of all seven major retinal cell types. Furthermore, we identified gene-expression differences between developing macula and periphery and between distinct populations of horizontal cells. We also identified species-specific patterns of gene expression during human and mouse retinal development. Finally, we identified an unexpected role for ATOH7 expression in regulation of photoreceptor specification during late retinogenesis. These results provide a roadmap to future studies of human retinal development and may help guide the design of cell-based therapies for treating retinal dystrophies.
