Gene regulatory networks controlling temporal patterning, neurogenesis, and cell-fate specification in mammalian retina
Pin Lyu,
Thanh Hoang,
Clayton P. Santiago,
Eric D. Thomas,
Andrew E. Timms,
Haley Appel,
Megan Gimmen,
Nguyet Le,
Lizhi Jiang,
Dong Won Kim,
Siqi Chen,
David F. Espinoza,
Ariel E. Telger,
Kurt Weir,
Brian S. Clark,
Timothy J. Cherry,
Jiang Qian,
Seth Blackshaw
Affiliations
Pin Lyu
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Thanh Hoang
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Clayton P. Santiago
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Eric D. Thomas
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Andrew E. Timms
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA 98101, USA
Haley Appel
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Megan Gimmen
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Nguyet Le
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Lizhi Jiang
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Dong Won Kim
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Siqi Chen
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
David F. Espinoza
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ariel E. Telger
Department of Ophthalmology and Visual Sciences, Brotman Baty Institute, Seattle, WA 98195, USA
Kurt Weir
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Brian S. Clark
Department of Ophthalmology and Visual Sciences, Brotman Baty Institute, Seattle, WA 98195, USA; Brotman Baty Institute, Seattle, WA 98195, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
Timothy J. Cherry
Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA 98101, USA; Brotman Baty Institute, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA
Jiang Qian
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Seth Blackshaw
Department of Ophthalmology, 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; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA and single-cell ATAC sequencing (scATAC-seq) analysis in developing mouse and human retina to identify multiple interconnected, evolutionarily conserved GRNs composed of cell-type-specific transcription factors that both activate genes within their own network and inhibit genes in other networks. These GRNs control temporal patterning in primary progenitors, regulate transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirm that NFI transcription factors selectively activate expression of genes promoting late-stage temporal identity in primary retinal progenitors and identify other transcription factors that regulate rod photoreceptor specification in postnatal retina. This study inventories cis- and trans-acting factors that control retinal development and can guide cell-based therapies aimed at replacing retinal neurons lost to disease.