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Thalamocortical organoids reveal axonogenesis phenotypes of 22q11.2 microdeletion [scRNA-seq]

ABSTRACT: Dysfunction of the thalamocortical pathway has been implicated in multiple psychiatric disorders, but mechanisms by which these defects emerge remain poorly understood. We explored this question in the context of the 22q11.2 microdeletion, which represents a significant genetic risk for schizophrenia, leveraging emerging technologies of in vitro brain organogenesis using chimeric brain organoids derived from human induced pluripotent stem cells. Here we show that the 22q11.2 microdeletion leads to transcriptional dysregulation in thalamic organoids that is enriched for psychiatric disease risk genes, including elevated expression of FOXP2, which represents the most significantly dysregulated transcription factor in glutamatergic neurons and astroctyes. In a co-culture model fusing thalamic and cortical organoids, we demonstrate that the 22q11.2 deletion mediates an overgrowth of thalamic axons via overexpression of FOXP2, which then subsequently mediates the overgrowth of reciprocal corticothalamic axons. Dysregulation of FOXP2 leads to downregulation of ROBO2, an axon repulsive receptor important for thalamocortical axon pathfinding, and knockdown of ROBO2 in control organoids phenocopies excessive outgrowth of thalamic axons. Together, our study suggests that early steps in thalamocortical pathway development may be dysregulated in a model of genetic risk for schizophrenia, and contribute to neural phenotypes in 22q11.2 microdeletion syndrome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245719 | GEO | 2024/02/22

REPOSITORIES: GEO

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Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

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Thalamocortical organoids reveal axonogenesis phenotypes of 22q11.2 microdeletion [scRNA-seq]

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