GAS1 is required for Notch-dependent facilitation of SHH signalling in forebrain development
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB43666 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5465080_1.fastq.gz | Fastqsanger.gz | |||
| ERR5465080_2.fastq.gz | Fastqsanger.gz | |||
| ERR5465081_1.fastq.gz | Fastqsanger.gz | |||
| ERR5465081_2.fastq.gz | Fastqsanger.gz | |||
| ERR5465082_1.fastq.gz | Fastqsanger.gz |
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Project description:A Gas1 knockout was made by replacing the Gas1 coding region with a LacZ gene. The ventral neuroepithelial midline of the rostral diencephalon of Gas1 wild type and mutant embryos at E10 were isolated using laser capture microdissection. In total five replicates for wild type and four replicates for Gas1 mutant embryos were analyzed. Each replicate consisted of a pool of five embryos of the respective genotype.
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Project description:Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations.
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Project description:We report the use of a light stimulus to geometrically confine SHH expression in neuralizing hESCs. This led to the self-organization of mediolateral neural patterns. scRNA-seq analysis established that these structures represent the dorsal-ventral forebrain, at the end of the first month of development. Here, we show that morphogen light-stimulation is a scalable tool that induces self-organizing centers.
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Project description:The generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. It is well known that Notch signalling pathway through the inhibition of proneural genes is a key regulator of neurogenesis in the vertebrate central nervous system. However, its role during hypothalamus formation along with its downstream effectors remains poorly defined. Here, we have transiently blocked Notch activity in chick embryos and used global gene expression analysis to provide evidence that Notch signalling modulates the generation of neurons in the early developing hypothalamus by lateral inhibition. Most importantly, we have taken advantage of this model to identify novel targets of Notch signalling, such as Tagln3 and Chga, which were expressed in hypothalamic neuronal nuclei. This data gives essential advances into the early generation of neurons in the hypothalamus. We demonstrate that inhibition of Notch signalling during early development of the hypothalamus enhances expression of several new markers. These genes must be considered as important new targets of the Notch/proneural network. Four sets of samples were used for analysing transcriptome changes in DAPT treated chicl embryos. The rostral part of the head (including the anterior forebrain, optic vesicles and overlying tissue) was collected from control embryos and DAPT-treated embryos at stage HH13.
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Project description:Self-organization of human dorsal-ventral forebrain structures by light induced SHH
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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:The interplay of positive and negative interactions between drug sensitive and resistant cells determines the efficacy of treatment in heterogeneous cancer cell populations. We studied isogenic estrogen receptor positive (ER+) breast cancer cell lineages sensitive and resistant to ribociclib-induced CDK4/6 inhibition in monoculture and coculture, finding that sensitive cells grow and compete more effectively in the absence of treatment. During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed facilitation in ecology. Several lines of evidence indicate estradiol production by resistant cells as the mechanism of facilitation, with both liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays and single cell RNA-seq showing higher production by resistant cells, and sensitive cells shifting phenotype to become more like resistant cells when grown in coculture. Adding estradiol in monoculture provides sensitive cells with partial resistance, and cancels facilitation in coculture. Mathematical modeling quantifies the strength of competition and facilitation, and predicts that blocking facilitation has the potential to control both resistant and sensitive cell populations and inhibit the emergence of a refractory population.
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Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to promote maintenance and proliferation of neural stem cells in the adult mouse forebrain. We have analyzed the gene expression pattern in neurogenic Shh-responding astroglia (= neural stem cells ) in the subventicular zone of the lateral ventricle and dentate gyrus of the hippocampus in comparison to the non-neurogenic Shh-responding glia (=Bergman glia) in the cerebellum to identify the genes specifically involved in neurogenic function downstream of Shh signaling. In this dataset, we include the expression data obtained from FACS-sorted Gli1+ GFAP+ cells from microdissected SVZ, hippocampus and cerebellum. GFAP expression is based on hGFAP-GFP reporter line and Gli1 expression is lineage marked using Gli1-CreER;ROSA26-tdTomato mice.
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Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to promote maintenance and proliferation of neural stem cells in the adult mouse forebrain. We have analyzed the gene expression pattern in neurogenic Shh-responding astroglia (= neural stem cells ) in the subventicular zone of the lateral ventricle and dentate gyrus of the hippocampus in comparison to the non-neurogenic Shh-responding glia (=Bergman glia) in the cerebellum to identify the genes specifically involved in neurogenic function downstream of Shh signaling. In this dataset, we include the expression data obtained from FACS-sorted Gli1+ GFAP+ cells from microdissected SVZ, hippocampus and cerebellum. GFAP expression is based on hGFAP-GFP reporter line and Gli1 expression is lineage marked using Gli1-CreER;ROSA26-tdTomato mice. 15 Total samples were analyzed. We compared expression levels of SVZ vs. Cerebellum, Hippocampus vs. Cerebelllum to identify genes which had more than 4 fold change in expression levels with p < 0.01. From this narrowed list, we compared between SVZ and Hippocampus to identify the common genes up and down regulated. In addition, we also identified commonly expressed genes in hippocampus and SVZ at high level.
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