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Mutations in distinct translation-dependent quality control pathways lead to convergent molecular pathogenesis and neurodevelopmental defects.

ABSTRACT: Mutations in distinct translation-dependent quality control pathways lead to convergent molecular pathogenesis and neurodevelopmental defects.

PROVIDER: PRJNA682206 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13186856.fastq.gz	Fastqsanger.gz
	SRR13186857.fastq.gz	Fastqsanger.gz
	SRR13186858.fastq.gz	Fastqsanger.gz
	SRR13186859.fastq.gz	Fastqsanger.gz
	SRR13186860.fastq.gz	Fastqsanger.gz

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Mutations in distinct translation-dependent quality control pathways lead to convergent molecular pathogenesis and neurodevelopmental defects.

Project description:Translation-dependent quality control pathways govern protein synthesis and proteostasis by degrading potentially toxic peptide products derived from aberrant mRNAs. However, little is known about the in vivo defects that arise in the absence of these pathways and how translation is altered in the absence of these pathways. Here, we demonstrate that the ribosome rescue factors Pelo/Hbs1l are both critical for embryonic and neuronal development but dispensable for neuronal survival in the adult brain. Loss of Pelo/Hbs1l in cerebellar progenitors impaired differentiation of these cells. Our analysis of Pelo/Hbs1l deficient fibroblasts revealed translational reprogramming of multiple pathways including mTORC1 signaling likely to restore cellular homeostasis. Interestingly, similar affects on the translatome, signaling pathways and neurogenesis were observed when we conditionally deleted Upf2 to inhibit NMD. These data reveal that translation-dependent quality control pathways, which set out to mitigate errors in translation and to clear defective peptide products and aberrant mRNAs can trigger similar cellular responses and neurodevelopmental abnormalities.

2021-03-15 | GSE162556 | GEO

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology.

Project description:Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2. Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.

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Neurodevelopmental and behavioral defects in congenital heart disease [methylation]

Project description:Neurodevelopmental and behavioral defects in congenital heart disease [methylation]

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Title: Neurodevelopmental and behavioral defects in congenital heart disease

Project description:Title: Neurodevelopmental and behavioral defects in congenital heart disease

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Enhanced gliogenesis and delayed maturation underpin the neurodevelopmental defects in Lowe syndrome

Project description:The activity of signaling pathways is required for coordinated cellular and physiological processes that lead to the normal development of brain structure and function. Mutations in OCRL, a phosphatidylinositol 4,5-bisphosphate (PIP₂) 5-phosphatase, lead to the neurodevelopmental disorder Lowe Syndrome (LS). However, the mechanism by which mutations in OCRL lead to the brain phenotypes observed in LS remains unclear.We found that LS patient-derived induced pluripotent stem cells (iPSCs), when differentiated into neural cultures, exhibited significantly reduced neuronal excitability along with increased expression of the astrocytic marker GFAP. Multiomic single-nucleus RNA and ATAC sequencing revealed an early fate switch of LS patient-derived neural stem cells (LSP-NSCs) toward gliogenesis. Pseudobulk analysis of snRNA-seq data showed increased levels of DLK1, a non-canonical Notch ligand, in LS patient NSCs. This was associated with elevated levels of cleaved Notch protein and increased expression of its transcriptional target HES5, indicating upregulated Notch signaling. Treatment of iPSC-derived brain organoids with an inhibitor of PIP5K1C, the lipid kinase responsible for synthesizing PIP₂, restored neuronal excitability and rescued Notch signaling defects in LS patient-derived organoid cultures. Overall, our results demonstrate a role for PIP₂-dependent regulation of Notch signaling, cell fate specification, and the development of neuronal excitability mediated by OCRL activity.

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Neurodevelopmental and behavioral defects in congenital heart disease [methylation]

Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.

2024-12-09 | GSE283525 | GEO

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