Barcoding Notch signaling in the developing brain
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1116548 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29181700.fastq.gz | Fastqsanger.gz | |||
| SRR29181701_1.fastq.gz | Fastqsanger.gz | |||
| SRR29181701_2.fastq.gz | Fastqsanger.gz | |||
| SRR29181702.fastq.gz | Fastqsanger.gz | |||
| SRR29181703.fastq.gz | Fastqsanger.gz |
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Project description:Developmental signaling inputs are fundamental for shaping cell fates and behavior. However, traditional fluorescent-based signaling reporters have limitations in scalability and molecular resolution of cell types. We present SABER-seq, a CRISPR-Cas molecular recorder that stores transient developmental signaling cues as permanent mutations in cellular genomes for deconstruction at later stages via single-cell transcriptomics. We applied SABER-seq to record Notch signaling in developing zebrafish brains. SABER-seq has two components: a signaling sensor and a barcode recorder. The sensor activates Cas9 in a Notch-dependent manner with inducible control while the recorder obtains mutations in ancestral cells where Notch is active. We combine SABER-seq with an expanded juvenile brain atlas to identify cell types derived from Notch-active founders. Our data reveals rare examples where differential Notch activity in ancestral progenitors is detected in terminally differentiated neuronal subtypes. SABER-seq is a novel platform for rapid, scalable and high-resolution mapping of signaling activity during development.
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Project description:Mechanisms guiding the induction of blood-brain barrier (BBB) properties in central nervous system (CNS) endothelial cells during human development are incompletely understood. To explore induction of reduced vesicular endocytosis and transcytosis properties in a human in vitro model of the BBB, we used human pluripotent stem cell (hPSC)-derived endothelial progenitor cells (EPCs) in which Wnt/β-catenin signaling was activated to generate hPSC-derived CNS-like ECs (hPSC-CECs). We assessed the effects of Notch signaling through overexpression of the Notch1 receptor intracellular domain (N1ICD). N1ICD overexpression in hPSC-CECs was induced by treatment with doxycycline (Dox), and hPSC-CECs were sorted into subpopulations by FACS based on high or low surface expression of CD144/VE-cadherin (CD144hi or CD144lo, respectively). Several negative control replicates treated with PBS (nearly all of which were CD144hi), were included as well. Our findings indicate that Notch signaling differentially regulates vesicular endocytosis and transcytosis-related genes in a human model of the developing BBB, contributing to our understanding of how Notch signaling induces these specific BBB properties in this model of human CNS EC development.
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Project description:Sivakumar2011 - Notch Signaling Pathway
Notch is a transmembrane receptor that mediates local cell-cell communication and coordinates a signaling cascade. It plays a key role in modulating cell fate decisions throughout the development of invertebrate and vertebrate species and the misregulation leads to a number of human diseases.
References:
Notch signaling: from the outside in.
Notch signaling in hematopoiesis and early lymphocyte development.
An overview of the Notch signalling pathway.
Notch and cancer: best to avoid the ups and downs.
Notch signaling: control of cell communication and cell fate.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
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Project description:Short term transition to high-fat diet (HFD) feeding causes rapid changes in the molecular architecture of the blood-brain-barrier (BBB), BBB permeability and brain glucose uptake. However, the precise mechanisms responsible for these changes remain elusive. Here we detected a rapid downregulation of Notch signaling after short-term HFD feeding. Conversely, Notch activation restores HFD-fed mouse serum induced reduction of Glut1 expression and glycolysis in cultured brain microvascular endothelial cells (BMECs). Selective, inducible expression of Notch-intracellular domain (IC) in BMECs prevents HFD-induced reduction of Glut1 expression and hypothalamic glucose uptake. Caveolin (Cav)-1 expression in BMECs is increased upon short term HFD feeding. However, NotchICBMECs mice display reduced caveola formation and BBB permeability. This ultimately translates into reduced hypothalamic insulin transport, action and systemic insulin sensitivity. Collectively, we highlight a critical role of Notch-signaling in the pleiotropic effects of short-term dietary transitions on BBB functionality.
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Project description:Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is currently treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to their mandibular bone, and thus offer an opportunity to understand how to boost intrinsic healing ability. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes. We also show that modulation of Notch signaling during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Notch signaling is required for mandibular bone healing, as pharmacological inhibition of Notch signaling blocks cartilage callus formation and results in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates regenerative ossification. Mechanistically, we report that postoperative Notch signaling regulates multiple phases of chondroid regeneration and patterns callus metabolic landscape. Given conserved functions of Notch signaling in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing may have therapeutic value.
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Project description:Maternal antibodies specific for antigens in the developing brain are implicated as risk factors for neurodevelopmental disorders, but how these antibodies interfere with neurodevelopment remain speculative. It has been postulated that immunoglobulin G-immune complexes (IgG-IC) activate Fc gamma receptors (FcγR) on non-immune cells in the brain, thereby modulating intracellular signaling and/or internalizing function-blocking antibodies specific for intracellular antigens. However, testing this hypothesis has been hindered by the paucity of data regarding FcγR in the developing brain. Thus, we first investigated FcγR expression in the brain of neonatal male and female rats using quantitative PCR analyses. FcgrIa, FcgrIIa, FcgrIIb, FcgrIIIa and Fcgrt transcripts were detectable in the cortex, hippocampus and cerebellum at postnatal days 1 and 7. These transcripts were also present in primary hippocampal and cortical cell cultures, where their expression was upregulated by IFNγ. In order to confirm protein abundance of FcγRIa, FcγRIIb and FcγRIIIa in cultured hippocampal and cortical neurons and astrocytes on the single cell and tissue level we used immunocytochemistry, western blotting, proteotype analysis, and flow cytometry. The data shows that a subpopulation of these cells co-express the excitatory FcγRIa and the inhibitory FcγRIIb. Functional analysis shows that exposure of hippocampal and cortical cell cultures to IgG-IC increased intracellular calcium and Erk phosphorylation, and triggered FcγR-mediated internalization of IgG. Collectively, these data demonstrate that developing neurons and astrocytes express signaling competent FcγR. which could establish a molecular mode of action of maternal antibodies could influence vulnerability to neurodevelopmental disorders via direct interactions with FcγR on non-immune cells in the developing brain. These findings support the hypothesis that maternal antibodies influence vulnerability to neurodevelopmental disorders via direct interactions with FcγR on non-immune cells in the developing brain.
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