ABSTRACT
The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.
Subject(s)
Gene Expression Regulation, Developmental , Retina , Single-Cell Analysis , Humans , Retina/embryology , Retina/metabolism , Retina/cytology , Retina/growth & development , Gene Regulatory Networks , Transcription Factors/metabolism , Transcription Factors/genetics , Cell Differentiation/genetics , Fetus , Cell Nucleus/metabolism , Cell Nucleus/genetics , Atlases as TopicABSTRACT
Regeneration of neurons has important implications for human health, and the retina provides an accessible system to study the potential of replacing neurons following injury. In previous work, we generated transgenic mice in which neurogenic transcription factors were expressed in Müller glia (MG) and showed that they stimulated neurogenesis following inner retinal damage. It was unknown, however, whether the timing or mode of injury mattered in this process. Here, we explored these parameters on induced neurogenesis from MG and show that MG expressing Ascl1 will generate new bipolar neurons with similar efficiency irrespective of injury mode or timing. However, MG that express Ascl1-Atoh1 produce a new type of retinal ganglion-like cell after outer retinal damage, which is absent with inner retinal damage. Our data suggest that although cell fate is primarily dictated by neurogenic transcription factors, the inflammatory state of MG relative to injury can influence the outcome of induced neurogenesis.