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bioRxiv · 10.1101/2023.03.22.533827

Self-formation of concentric zones of telencephalic and ocular tissues and directional retinal ganglion cell axons

Liu, W.·Shrestha, R.·Lowe, A.·Zhang, X.·Spaeth, L.
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Abstract

The telencephalon and eye in mammals are originated from adjacent fields at the anterior neural plate. Morphogenesis of these fields generates telencephalon, optic-stalk, optic-disc, and neuroretina along a spatial axis. How these telencephalic and ocular tissues are specified coordinately to ensure directional retinal ganglion cell (RGC) axon growth is unclear. Here, we report the self-formation of human telencephalon-eye organoids comprising concentric zones of telencephalic, optic-stalk, optic-disc, and neuroretinal tissues along the center-periphery axis. Initially-differentiated RGCs grew axons towards and then along a path defined by adjacent PAX2+ optic-disc cells. Single-cell RNA sequencing of CONCEPT organoids not only confirmed telencephalic and ocular identities but also identified expression signatures of early optic-disc, optic-stalk, and RGCs. These signatures were similar to those in human fetal retinas. Optic-disc cells in CONCEPT organoids differentially expressed FGF8 and FGF9; FGFR inhibitions drastically decreased RGC differentiation and directional axon growth. Through the identified RGC-specific cell-surface marker CNTN2, electrophysiologically-excitable RGCs were isolated under a native condition. Our findings provide insight into the coordinated specification of early telencephalic and ocular tissues in humans and establish resources for studying RGC-related diseases such as glaucoma. Impact statementA human telencephalon-eye organoid model that exhibited axon growth and pathfinding from retinal ganglion cell (RGC) axons is reported; via cell surface marker CNTN2 identified using scRNA-seq, early RGCs were isolated under a native condition.

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Liu, W., Shrestha, R., Lowe, A., Zhang, X., Spaeth, L.. 2023-03-24. Self-formation of concentric zones of telencephalic and ocular tissues and directional retinal ganglion cell axons. https://doi.org/10.1101/2023.03.22.533827

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