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Single cell RNA-sequencing of Bardet Biedl Syndrome iPSC-derived hypothalamic neurons

ABSTRACT: Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and characterized by hyperphagic obesity. We developed a cellular model of BBS using induced pluripotent stem cell (iPSCs)-derived hypothalamic arcuate-like neurons. Single-cell RNA sequencing of iPSC-derived hypothalamic neurons from BBS1M390R and isogenic control identified affected cell subpopulations and several down-regulated pathways in BBS1 hypomorphic neurons, including axon guidance, insulin signaling and cAMP pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164891 | GEO | 2021/09/01

REPOSITORIES: GEO

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Project description:<h4>Summary</h4>Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a new bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on isolated OSs show that Bbs1 is required for BBSome-entry into OSs and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a new role for Bbs1/BBSome in OS lipid homeostasis and suggest a new pathomechanism underlying retinal degeneration in BBS. Data availability:The proteomic data generated in this study have been deposited in PRIDE repository under accession code <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD026646' rel='noopener noreferrer' target='_blank'>PXD026646</a> for the OS proteome and <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD030522' rel='noopener noreferrer' target='_blank'>PXD030522</a> for the whole eye lysate proteome [<a href='https://www.ebi.ac.uk/pride' rel='noopener noreferrer' target='_blank'>https://www.ebi.ac.uk/pride</a>].The RNAseq data generated in this study have been deposited in the SRA repository under the BioProject accession number PRJNA789116 [<a href='https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA789116' rel='noopener noreferrer' target='_blank'>https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA789116</a>].

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Single cell RNA-sequencing of Bardet Biedl Syndrome iPSC-derived hypothalamic neurons

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