Self-formation of concentric zones of telencephalic and ocular tissues and directional retinal ganglion cell axons
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ABSTRACT:
PROVIDER: PRJNA789332 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17244176_1.fastq.gz | Fastqsanger.gz | |||
| SRR17244176_2.fastq.gz | Fastqsanger.gz |
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Project description:Telencephalon, optic stalk, and optic-cup in vertebrates are originated from adjacent fields in the anterior neuroplate. How these tissues develop coordinately along the midline-periphery axis is unclear. Here, we report the self-formation of a human telencephalon-eye organoid comprising concentric zones of FOXG1+ telencephalon, PAX2+ optic disc/stalk, VSX2+ neuroretina, and PAX6+ tissues along the center-periphery axis. FGFs and BMPs were expressed starting at early stages and subsequently exhibited concentric gradients, suggesting their involvement in tissue patterning and coordinated cell differentiation. Early differentiated retinal ganglion cells (RGC) grew axons towards and along a path defined by an adjacent PAX2+ cell population. Lens cells were also found. Single-cell RNA sequencing confirmed telencephalic and ocular cell identities, located PAX2+ cell populations mimicking the optic disc/stalk, and identified RGC-specific cell surface protein CNTN2. RGCs were isolated in one step via CNTN2 in a native condition, facilitating therapeutic development for RGC-related retinal diseases such as glaucoma.
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Project description: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 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+ VSX2+ optic-disc cells. Single-cell RNA sequencing of these 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 these organoids differentially expressed FGF8 and FGF9; FGFR inhibitions drastically decreased early RGC differentiation and directional axon growth. Through the RGC-specific cell-surface marker CNTN2 identified here, 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.
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Project description:Local mRNA translation mediates the adaptive responses of axons to extrinsic signals but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles suggesting distinct steps in axon wiring, such as elongation, pruning and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and novel sequence elements generated by alternative splicing that promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo. The profiling of ribosome-bound mRNAs in mouse retinal ganglion cell axons at 4 different developmental stages
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Project description:Experimental ocular hypertension (IOP) induces senescence of retinal ganglion cells (RGCs) that mimicks events occurring in human glaucoma. An established transgenic p16-3MR mouse model in which the systemic administration of the small molecule ganciclovir (GCV) selectively kills p16INK4a-expressing cells was used to compare transcriptomes of retinas from IOP and control eyes in GCV-treated and non-treated mice, to investigate how experimental removal of senescent p16INK4a-positive cells impacts retinal cells in conditions resembling glaucoma.
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Project description:Human telencephalon is an evolutionary advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remains largely unknown. We generated human telencephalic organoids from stem cell-derived single neural rosettes (SNRs) and investigated telencephalic development under normal and pathological conditions. SNR-derived organoids contained pallial and subpallial neural progenitors (NPs), excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and demonstrated predictable organization and cytoarchitecture. We comprehensively characterized the properties of neurons in SNR-derived organoids and identified transcriptional programs associated with the specification of+B50:B51 excitatory and inhibitory lineages from a common pool of NPs early in telencephalic development. We also demonstrated that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits associated with impaired expression of clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable new model for studying human telencephalic development and identifies novel molecular pathways disrupted by SHANK3 hemizygosity in human telencephalic tissue.
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Project description:Human telencephalon is an evolutionary advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remains largely unknown. We generated human telencephalic organoids from stem cell-derived single neural rosettes (SNRs) and investigated telencephalic development under normal and pathological conditions. SNR-derived organoids contained pallial and subpallial neural progenitors (NPs), excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and demonstrated predictable organization and cytoarchitecture. We comprehensively characterized the properties of neurons in SNR-derived organoids and identified transcriptional programs associated with the specification of+B50:B51 excitatory and inhibitory lineages from a common pool of NPs early in telencephalic development. We also demonstrated that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits associated with impaired expression of clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable new model for studying human telencephalic development and identifies novel molecular pathways disrupted by SHANK3 hemizygosity in human telencephalic tissue.
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