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Specification of a rostro-caudal axis in cortical assembloids through a polarized source of FGF8

ABSTRACT: Specification of a rostro-caudal axis in cortical assembloids through a polarized source of FGF8

PROVIDER: PRJNA963209 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14664005.fastq.gz	Fastqsanger.gz
	SRR14664006.fastq.gz	Fastqsanger.gz
	SRR14664007.fastq.gz	Fastqsanger.gz
	SRR14664008.fastq.gz	Fastqsanger.gz
	SRR14664009.fastq.gz	Fastqsanger.gz

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Specification of a rostro-caudal axis in cortical assembloids through a polarized source of FGF8 (scRNA-Seq)

Project description:Current organoid protocols are widely used to mechanistically study cortical development, evolution and brain pathologies. While these systems generate all major cortical cell types in histologically distinct compartments, they lack cortical area topography, which is initiated by gradients of signaling molecules released by signaling organizers that establish transcriptionally distinct domains along the rostro-caudal axis of the developing cortex. Here, we engineer human cortical assembloids that combine an organizer-like structure expressing FGF8 with an elongated organoid design to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. We demonstrate that individual polarized cortical assembloids (polCA) mount a position-dependent transcriptional program that matches the in vivo rostro-caudal gene expression patterns. Importantly, positional identity is lost in polCA carrying a mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability in humans. Similar to in vivo, this program is accompanied by transcriptional divergence of radial glia cells and excitatory neurons and their segregation along the longitudinal axis of individual organoids. Thus, this method reproduces in vivo cortical topography in individual organoids and enables the analysis of area-related phenotypes underlying human disorders.

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Specification of a rostro-caudal axis in cortical assembloids through a polarized source of FGF8

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A polarized FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids.

Project description:Organoids generating major cortical cell types in distinct compartments are used to study cortical development, evolution and disorders. However, the lack of morphogen gradients imparting cortical positional information and topography in current systems hinders the investigation of complex phenotypes. Here, we engineer human cortical assembloids by fusing an organizer-like structure expressing fibroblast growth factor 8 (FGF8) with an elongated organoid to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. These polarized cortical assembloids mount a position-dependent transcriptional program that in part matches the in vivo rostrocaudal gene expression patterns and that is lost upon mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability. By producing spatially oriented cell populations with signatures related to frontal and temporal area identity within individual assembloids, this model recapitulates in part the early transcriptional divergence embedded in the protomap and enables the study of cortical area-relevant alterations underlying human disorders.

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