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. Lu et al. performed scRNA-seq on the developing human retina and retinal organoids. Using comprehensive analyses, they deduced mechanisms regulating human retinal cell-fate specification and foveagenesis and contrasted these with murine retinal development. The data are a valuable resource for understanding human retinal development and disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 473-491.e9 |
| Journal | Developmental Cell |
| Volume | 53 |
| Issue number | 4 |
| DOIs | |
| State | Published - May 18 2020 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank J. Nathans, A. Kolodkin, R. Johnston Jr., S. Chen, P. Ruzycki, and W. Yap for comments on the manuscript. We thank the Transcriptomics and Deep Sequencing Core at Hopkins for assistance in sequencing and Dr. Jeff Wrana and Daniel Trcka for technical assistance with preparing single-cell libraries and both the Morgentaler Clinic in Toronto and the donors for access to developing retinal tissue. We also thank Xin Zhou, Michael Dyer, and Jian Wang (St. Jude Children’s Research Hospital) for help with hosting the scRNA-seq dataset. This work was supported by the Canadian Institute for Health Research (CIHR) grant # 153128 (R.B.), the Krembil Foundation (R.B.), the Strategic Priority Research Program of the Chinese Academy of Sciences grants XDA16020601 and XDB32010100 (X.W.), National Basic Research Program of China grants 2019YFA0110100 , 2017YFA0102601 , and 2017YFA0103303 (X.W.), the National Natural Science Foundation of China (NSFC) grants 91732301 , 31671072 , 31771140 , and 81891001 (X.W.), the Grants of Beijing Brain Initiative of Beijing Municipal Science & Technology Commission Z181100001518004 (X.W.), the National Science Fund for Distinguished Young Scholars of China grant 81925009 (T.X.), the National Natural Science Foundation of China grant 81790644 (T.X.), and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences at Washington University from Research to Prevent Blindness (B.S.C.).
Funding Information:
We thank J. Nathans, A. Kolodkin, R. Johnston Jr. S. Chen, P. Ruzycki, and W. Yap for comments on the manuscript. We thank the Transcriptomics and Deep Sequencing Core at Hopkins for assistance in sequencing and Dr. Jeff Wrana and Daniel Trcka for technical assistance with preparing single-cell libraries and both the Morgentaler Clinic in Toronto and the donors for access to developing retinal tissue. We also thank Xin Zhou, Michael Dyer, and Jian Wang (St. Jude Children's Research Hospital) for help with hosting the scRNA-seq dataset. This work was supported by the Canadian Institute for Health Research (CIHR) grant #153128 (R.B.), the Krembil Foundation (R.B.), the Strategic Priority Research Program of the Chinese Academy of Sciences grants XDA16020601 and XDB32010100 (X.W.), National Basic Research Program of China grants 2019YFA0110100, 2017YFA0102601, and 2017YFA0103303 (X.W.), the National Natural Science Foundation of China (NSFC) grants 91732301, 31671072, 31771140, and 81891001 (X.W.), the Grants of Beijing Brain Initiative of Beijing Municipal Science & Technology Commission Z181100001518004 (X.W.), the National Science Fund for Distinguished Young Scholars of China grant 81925009 (T.X.), the National Natural Science Foundation of China grant 81790644 (T.X.), and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences at Washington University from Research to Prevent Blindness (B.S.C.). Y.L. F.S. W.Y. S.L. Q.W. J.D.P. A.K. S.Z. T.H. Z.Z. F.Z. M.Z. N.T. Y.Z. S.H. J.Z. and B.S.C. performed experiments and analyses associated with the manuscript. G.L.S. T.D.S. E.J.F. and L.A.G. guided cross-species bioinformatic analyses with E.J.F. and L.A.G. serving as senior bioinformaticians. Study design was conceptualized by T.X. R.B. S.B. X.W. and B.S.C. with assistance from X.D. E.J.F. L.A.G. D.J.Z. and J.T.H. F.S. R.B. S.B. X.W. and B.S.C. wrote the paper with input from all co-authors. The authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Inc.
Keywords
- cell fate
- fovea
- gene regulatory networks
- neurogenesis
- neurogenic bHLH factor
- organoid
- patterning
- retina
- single cell RNA-seq
- transcription factors