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Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels

ABSTRACT: Purpose: Exploring mechanisms defining the unique nature of vascular development and differentiation in the brain . Methods: High-resolution gene expression profiles of embryonic endothelial cells (EC) using translating ribosome affinity purification (TRAP) and single cell RNA-sequencing. RNA-sequenzing of transcription factor infected HUVEC. Results: Comparisons of different organ-, temporal- or Ctnnb1 knock out-specific vascular translatomes revealed extensive molecular changes during the unique development of the brain endothelium. We identified brain endothelial-specific transcription factors – Foxf2, Foxl2, Foxq1, Lef1, Ppard, Zfp551 and Zic3 – that are associated with the temporal maturation of the blood-brain barrier and act downstream of the Wnt/Ctnnb1 signaling pathway. Profiling individual EC revealed a remarkable heterogeneity. Nevertheless, high levels of Foxf2, Foxq1, Ppard and Zic3 were correlated with elevated expression of differentiation markers. This could be recapitulated in vitro, where expression of Foxf2 and Zic3 in HUVEC led to an induction of blood-brain barrier differentiation markers. Conclusions: Our study provides further insights into the temporal and cellular complexity of the developing embryonic brain endothelium. Our data raises many questions and provides a basis for further studies aiming to unravel cellular and molecular mechanisms that underlie vascular development and differentiation in the CNS. We anticipate that additional investigation of the identified transcription factors is likely to be a fruitful approach in understanding and manipulating the development of BBB and to engineer more advanced blood brain barrier in vitro models.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE79306 | GEO | 2017/07/12

SECONDARY ACCESSION(S): PRJNA315441

REPOSITORIES: GEO

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Project description:Transcription factor Foxq1 controls mucin gene expression and granule content in mouse stomach surface mucous cells ; Background and Aims: The gastric mucosa provides a stringent epithelial barrier and produces acid and enzymes that initiate digestion. In this regenerating tissue, progenitors differentiate continually into 4 principal specialized cell types, yet underlying mechanisms of differentiation are poorly understood. We identified stomach-restricted expression of the forkhead transcription factor FOXQ1. Methods: We used a combination of genetic, histochemical, ultrastructural and molecular analysis to study gastric cell lineages with respect to FOXQ1. Results: Within the developing and adult gastrointestinal tract, Foxq1 mRNA is restricted to the stomach, expressed prominently in foveolar (pit) cells, the abundant mucin-producing cells that line the mucosal surface, and required for their complete differentiation. Mice carrying Foxq1 coding mutations show virtual absence of mRNA and protein for the backbone of the predominant stomach mucin, MUC5AC. These observations correspond to a paucity of foveolar-cell secretory vesicles and notable loss of stomach but not intestinal mucus. Transcriptional profiling identified a surprisingly restricted set of genes with altered expression in Foxq1 mutant stomachs. MUC5AC is a highly tissue-restricted product that similarly depends on FOXQ1 in its other major site of expression, conjunctival goblet cells. Conclusions: Taken together, these observations imply that promotion of gastric MUC5AC synthesis is a primary, cell-autonomous function of FOXQ1. This study is the first to implicate a transcription factor in terminal differentiation of foveolar cells and begins to define the requirements to assemble highly specialized organelles and cells in the gastric mucosa. DOI: 10.1053/j.gastro.2008.04.019 Experiment Overall Design: RNA from stomach antrum from 2 of each Satin, Beige, and BL6 mice were compared using microarray analysis.

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Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels

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