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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [scRNA-Seq]

ABSTRACT: During mammalian embryogenesis, axial elongation of the neural tube is critical for establishing the anterior-posterior body axis, but is difficult to interrogate directly because it occurs post-implantation. Here we report an organoid model of neural tube extension using human pluripotent stem cell (hPSC) aggregates that recapitulates the morphologic and temporal gene expression patterns of neural tube development. Axially extending organoids consisted of longitudinally elongated epithelial compartments and contained TBXT(+)SOX2(+) neuromesodermal progenitors, PAX6(+) Nestin(+) neural progenitor populations, and MEOX1(+) paraxial mesoderm populations. Wnt agonism stimulated axial extensions in a dose-dependent manner and elongated organoids displayed regionalized rostral-caudal HOX gene expression, with hindbrain (HOXB1) expression distinct from brachial (HOXC6) and thoracic (HOXB9) expression. CRISPR interference-mediated silencing of BMP inhibitors induced elongation phenotypes that mimicked murine knockout models, and knock-down of the downstream Wnt target, TBXT, increased neuroepithelial compartmentalization and resulted in multiple extensions. These results indicate the potent morphogenic capacity of hPSC organoids to undergo axial elongation in a manner that can be used to dissect the cellular organization and patterning decisions that dictate early human nervous system development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155383 | GEO | 2021/05/28

REPOSITORIES: GEO

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Project description:Decrease in Cdx dosage in an allelic series of mouse Cdx mutants leads to progressively more severe posterior vertebral defects. These defects are corrected by posterior gain of function of the Wnt effector Lef1. Precocious expression of Hox paralogous 13 genes also induces vertebral axis truncation by antagonizing Cdx function. We report here that the phenotypic similarity also applies to patterning of the caudal neural tube and uro-rectal tracts in Cdx and Wnt3a mutants, and in embryos precociously expressing Hox13 genes. Cdx2 inactivation after placentation leads to posterior defects including incomplete uro-rectal septation. Compound mutants carrying one active Cdx2 allele in the Cdx4 null background (Cdx2/4), transgenic embryos precociously expressing Hox13 genes, and a novel Wnt3a hypomorph mutant all manifest a comparable phenotype with similar urorectal defects. Phenotype and transcriptome analysis in early Cdx mutants, genetic rescue experiments and gene expression studies lead us to propose that Cdx transcription factors act via Wnt signalling during the laying down of urorectal mesoderm, and that they are operative in an early phase of these events, at the site of tissue progenitors in the posterior growth zone of the embryo. Cdx and Wnt mutations and premature Hox13 expression also cause similar neural dysmorphology including ectopic neural structures sometimes leading to neural tube splitting at caudal axial levels. These findings involve the Cdx genes, canonical Wnt signalling, and the temporal control of posterior Hox gene expression in posterior morphogenesis in the different embryonic germ layers. They shed a new light on the etiology of the Caudal Dysplasia or Caudal Regression range of human congenital defects. We used dissected Cdx2 null mutant versus wild type embryos at the 4/5 somite and 7/8 somite stage. RNA was isolated from the posterior part of the embryos (20 embryos of each genotype and stage), dissected at the same axial levels by using the last somite boundary and the base of the allantois as landmarks. Differentially labelled cRNA from the Cdx2 and control embryos were hybridized on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments and two technical replicates, resulting in eight individual arrays.

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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [scRNA-Seq]

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