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NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [CHIR99021]

ABSTRACT: NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [CHIR99021]

PROVIDER: PRJNA848827 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19639052_1.fastq.gz	Fastqsanger.gz
	SRR19639052_2.fastq.gz	Fastqsanger.gz
	SRR19639053_1.fastq.gz	Fastqsanger.gz
	SRR19639053_2.fastq.gz	Fastqsanger.gz
	SRR19639054_1.fastq.gz	Fastqsanger.gz

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NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [CHIR99021]

Project description:WNT activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human trophoblast stem (TS) cells, activation of canonical WNT signaling is a key to maintenance of the TS cell stem state. NOTUM, a negative regulator of canonical WNT signaling, was prominently expressed in first trimester EVT cells developing in situ and upregulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for human TS cell differentiation to EVT cells. Canonical WNT signaling is essential for maintaining human trophoblast cell stemness and prevention of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for EVT cell differentiation.

2024-03-06 | GSE206034 | GEO

NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [Notum knockdown]

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NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [Notum knockdown]

Project description:NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT [Notum knockdown]

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NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT

Project description:NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT

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Wnt signaling activation confers a syncytiotrophoblast progenitor state on trophoblast stem cells of cynomolgus monkey.

Project description:Trophoblast stem cells (TSCs), derived from the trophectoderm of the blastocyst, are used as an in vitro model to reveal the underlying mechanisms of placentation in the mammal. In humans, suitable culture conditions for TSC derivation have been recently discovered. The established human TSCs differentiate efficiently toward two trophoblast subtypes, i.e., syncytiotrophoblast (STB) and extravillous trophoblast. On the other hand, the differentiation efficiencies were lower in macaque TSCs compared to human TSCs. Here, we demonstrate that the activation of Wnt signaling induced trophoblastic lineage switching to STB progenitor state. macTSCs highly expressed STB progenitor markers and obtained forskolin responsiveness by CHIR99021 treatment.

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Steroid Receptor Coactivator-2 Controls Human Extravillous Trophoblast Cell Proliferation, Migration, and Invasion

Project description:Abnormal placentation is a fundamental cause of pregnancy complications including preeclampsia, miscarriage, and intrauterine growth restriction. Proliferation, differentiation, migration, and invasion are key properties of trophoblast cells that regulate trophoblast functions. Imbalance of these cellular processes is linked to placental pathologies. Using HTR-8/SVneo immortalized human trophoblast cells, we demonstrate that steroid receptor coactivator-2 (SRC-2), a transcriptional regulator of nuclear receptors, is essential for extravillous trophoblast cell proliferation, migration, and invasion. Genome-wide transcriptomics identified an SRC-2–dependent transcriptome in HTR-8/SVneo cells that includes a diverse spectrum of proteins involved in placental tissue development and function. To emphasize the utility of this transcriptomics data set, we demonstrate that WNT family member 9A (WNT9A) is not only a molecular target of SRC-2 but also crucial for maintaining many of the cellular properties of human extravillous trophoblast cells.

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Design of a potent, selective and brain penetrant inhibitor of Wnt-deactivating enzyme Notum by optimization of a crystallographic fragment hit

Project description:Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human disease such as colorectal cancer and Alzheimer’s disease supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we describe the discovery and profile of 8I (ARUK3001185) as a potent, selective and brain pentrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identifed a pair of outstanding hits. Fragment development of these delivered 8I that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in proteomic and pharmacology screens showed 8I to be selective against serine hydrolases, kinases and drug targets.

2022-06-09 | PXD031338 | Pride

Unveiling the Temporal Dynamics of Mesenchymal Condensations in Tracheal Development through Non-Canonical Wnt Signaling and Notum

Project description:The trachea is essential for proper airflow to the lungs for gas exchange. Frequent congenital tracheal malformations affect the cartilage, causing the collapse of the central airway during the respiratory cycle. We have shown that Notum, a Wnt ligand de-acylase that attenuates the canonical branch of the Wnt signaling pathway, is necessary for cartilaginous mesenchymal condensations. In Notum deficient tracheas, chondrogenesis is delayed, and the trachea is stenotic. It is unknown if Notum attenuates non-canonical Wnt signaling. Notably, after mesenchymal deletion of the non-canonical Wnt5a ligand, we observed premature tracheal chondrogenesis. We hypothesize that Notum and Wnt5a are required to mediate the timely formation of mesenchymal condensations, giving rise to the tracheal cartilage. Ex vivo culture of tracheal tissue shows that chemical inhibition of the Wnt non-canonical pathway promotes earlier condensations, while Notum inhibition presents delayed condensations. Furthermore, non-canonical Wnt induction prevents the formation of cartilaginous mesenchymal condensations. On the other hand, cell-cell interactions among chondroblasts increased in the absence of mesenchymal Wnt5a. By performing an unbiased analysis of the gene expression in Wnt5a and Notum deficient tracheas, we detected that mRNA of genes essential for chondrogenesis and extracellular matrix formation are upregulated by E11.5 in Wnt5a mutants. The expression profile supports the premature and delayed chondrogenesis observed in Wnt5a and Notum deficient tracheas. We conclude that Notum and Wnt5a are necessary for proper tracheal cartilage patterning by coordinating timely chondrogenesis. Thus, these studies shed light on molecular mechanisms underlying congenital anomalies of the trachea.

2025-02-28 | GSE260707 | GEO

Genes regulated by pharmacological Wnt activation by CHIR99021 in the embryonic mouse cochlea

Project description:Our studies showed that Wnt activation influenced patterning of the mouse cochlea across the radial axis. To identify genes responding to Wnt activation, mouse embryonic cochleas were treated in the presence and absence of the GSK 3beta inhibitor, CHIR99021. Cochleas were harvested on E12.5 and cultured in vitro for 24 hours. On the next day (day 1), cochleas were treated with either DMSO vehicle control or CHIR99021. The 6-hour treatment helped to identify the immediate genes transcribed following Wnt activation.

2024-03-01 | GSE256069 | GEO

Notum Regulates the Cusp and Root Patterns in Mouse Molar

Project description:Notumis a direct target of Wnt/β-catenin signaling and plays a crucial role as a Wnt inhibitor within a negative feedback loop. In the tooth, Notum is known to be expressed in odontoblasts, and severe dentin defects and irregular tooth roots have been reported in Notum-deficient mice. However, the precise expression pattern of Notum in early tooth development, and the role of Notum in crown and root patterns remain elusive. In the present study, we identified a novel Notum expression in primary enamel knot (EK), secondary EKs, and dental papilla during tooth development. Notum-deficient mice exhibited enlarged secondary EKs, resulting in broader cusp tips, altered cusp patterns, and reduced concavity in crown outline. These alterations in crown outline led to a reduction in cervical tongue length, thereby inducing root fusion in Notum-deficient mice. Overall, these results suggest that the size of secondary EK size, regulated by the Wnt/Notum negative feedback loop, has a significant impact on the patterns of crown and root during tooth morphogenesis.

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