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

doi:10.1016/j.devcel.2020.04.009

Single-Cell Analysis of Human Retina Identifies Evolutionarily Conserved and Species-Specific Mechanisms Controlling Development

Dev Cell. 2020 May 18;53(4):473-491.e9. doi: 10.1016/j.devcel.2020.04.009. Epub 2020 May 7.

Authors

Yufeng Lu¹, Fion Shiau², Wenyang Yi³, Suying Lu⁴, Qian Wu⁵, Joel D Pearson⁴, Alyssa Kallman⁶, Suijuan Zhong¹, Thanh Hoang⁷, Zhentao Zuo⁸, Fangqi Zhao⁹, Mei Zhang¹⁰, Nicole Tsai¹¹, Yan Zhuo⁸, Sheng He⁸, Jun Zhang⁹, Genevieve L Stein-O'Brien⁷, Thomas D Sherman¹², Xin Duan¹¹, Elana J Fertig¹³, Loyal A Goff¹⁴, Donald J Zack¹⁵, James T Handa⁶, Tian Xue¹⁶, Rod Bremner¹⁷, Seth Blackshaw¹⁸, Xiaoqun Wang¹⁹, Brian S Clark²⁰

Affiliations

¹ 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.
² John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁹ Obstetrics and Gynecology Medical Center of Severe Cardiovascular of Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
¹⁰ 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.
¹¹ Departments of Ophthalmology and Physiology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹³ 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.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.

Abstract

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.

Keywords: cell fate; fovea; gene regulatory networks; neurogenesis; neurogenic bHLH factor; organoid; patterning; retina; single cell RNA-seq; transcription factors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged, 80 and over
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Biological Evolution*
Cell Differentiation
Female
Gene Expression Regulation, Developmental*
Humans
Mice
Organogenesis*
Retina / cytology*
Retina / metabolism
Retinal Cone Photoreceptor Cells / cytology
Retinal Cone Photoreceptor Cells / metabolism*
Single-Cell Analysis / methods*
Species Specificity

Substances

ATOH7 protein, human
Basic Helix-Loop-Helix Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding