Selective activation of FZD2 and FZD7 reveals non-redundant function during mesoderm differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1111090 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29009237.fastq.gz | Fastqsanger.gz | |||
| SRR29009238.fastq.gz | Fastqsanger.gz | |||
| SRR29009239.fastq.gz | Fastqsanger.gz | |||
| SRR29009240.fastq.gz | Fastqsanger.gz | |||
| SRR29009241.fastq.gz | Fastqsanger.gz |
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Project description:Wnt-ßcatenin signalling controls stem cell self-renewal and cell fate decisions and therefore its precise control could influence differentiation protocols efficiency and cell therapy efforts. During gastrulation, Wnt-ßcatenin signalling dictates lineage bifurcation choices leading from pluripotency to distinct primitive streak patterning, ultimately resulting in various mesendoderm cell types. However, the nature of the Wnt receptors involved in this process and how their signaling dynamics impact mesoderm specification remain elusive. Here, we used selective Frizzled and LRP5/6 antibody-based agonists (FLAgs) to investigate the function and activation kinetics of Frizzled receptor complexes during directed mesoderm differentiation of hPSCs. We found that FZD2 and FZD7 are expressed at the surface of hPSCs and that their activation triggers ßcatenin signaling with different kinetics thereby influencing mesoderm patterning choices. Using bulk and single-cell RNA sequencing, we showed that FZD7 activation promotes lineage commitment towards both paraxial and lateral mesoderm whereas FZD2 engagement preferentially induces paraxial mesoderm. Mechanistically, our results demonstrate that although the short-term response following FZD2 and FZD7 activation is similar, ßcatenin signaling kinetics differs. FZD2 activation results in a sustained Wnt activation profile that drives hPSCs differentiation to paraxial mesoderm while blocking lateral mesoderm. In contrast, FZD7 activation kinetics consists of a similar initial activation followed by dampening of the response to a low level of ßcatenin signaling that is permissive for lateral mesoderm induction in addition to paraxial mesoderm specification. Our results suggest that the function of FZD2 and FZD7 during mesoderm specification is non-redundant and that their selective activation to temporally modulate Wnt-ßcatenin signaling can be leveraged for precise directed differentiation outcomes.
2025-03-05 | GSE267334 | GEO
Project description:During gastrulation, Wnt-β-catenin signaling dictates lineage bifurcation generating different mesoderm cell types. However, the specific role of Wnt receptors in mesoderm specification remains elusive. Using selective Frizzled (FZD) and LRP5/6 antibody-based agonists, we examined FZD receptors' function during directed mesoderm differentiation of human pluripotent stem cells (hPSCs). We found that FZD2 and FZD7 receptors are expressed at the membrane of hPSCs and that their activation triggers β-catenin signaling with different kinetics, thereby influencing mesoderm patterning choices. Specifically, FZD7 activation enhances both paraxial and lateral mesoderm differentiation, whereas FZD2 activation favors paraxial mesoderm. Mechanistically, FZD2 activation promotes sustained Wnt-β-catenin levels, guiding hPSCs differentiation toward paraxial mesoderm, while blocking lateral mesoderm. In contrast, FZD7 activation kinetics display similar initial activation but more dampening of β-catenin signaling, permitting lateral mesoderm induction in addition to paraxial mesoderm specification. Our findings reveal non-redundant roles for FZD2 and FZD7 in mesoderm specification, offering leverage for precise directed differentiation outcomes.
| S-EPMC11864152 | biostudies-literature
Project description:Selective activation of FZD7 in human pluripotent stem cells
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Project description:Human pluripotent stem cells ( (H1/WA01/NIH stem cell registry number 0043) were treated with WNT3a protein, a FZD7-specific WNT mimetic, and a GSK3 inihibitor in time series to determine genes differentially upregulated and downregulated across all conditions or within one condition only.
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Project description:Mbodj2016 - Mesoderm specification during
Drosophila development
This model is described in the article:
Qualitative Dynamical
Modelling Can Formally Explain Mesoderm Specification and
Predict Novel Developmental Phenotypes.
Mbodj A, Gustafson EH, Ciglar L,
Junion G, Gonzalez A, Girardot C, Perrin L, Furlong EE, Thieffry
D.
PLoS Comput. Biol. 2016 Sep; 12(9):
e1005073
Abstract:
Given the complexity of developmental networks, it is often
difficult to predict the effect of genetic perturbations, even
within coding genes. Regulatory factors generally have
pleiotropic effects, exhibit partially redundant roles, and
regulate highly interconnected pathways with ample cross-talk.
Here, we delineate a logical model encompassing 48 components
and 82 regulatory interactions involved in mesoderm
specification during Drosophila development, thereby providing
a formal integration of all available genetic information from
the literature. The four main tissues derived from mesoderm
correspond to alternative stable states. We demonstrate that
the model can predict known mutant phenotypes and use it to
systematically predict the effects of over 300 new, often
non-intuitive, loss- and gain-of-function mutations, and
combinations thereof. We further validated several novel
predictions experimentally, thereby demonstrating the
robustness of model. Logical modelling can thus contribute to
formally explain and predict regulatory outcomes underlying
cell fate decisions.
This model is hosted on
BioModels Database
and identified by:
MODEL1607310000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-10-25 | MODEL1607310000 | BioModels
Project description:Single cell technologies hold promise for resolving complex early developmental phenotypes. Here we define a novel Hedgehog (Hh)-Fibroblast Growth Factor (FGF) signaling axis for the formation of anterior mesoderm lineages during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations—culminating in defects to anterior embryonic structures including the pharyngeal arches, heart, and anterior somites. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and FGF signaling for mesoderm migration. Mesoderm-specific Fgf4/Fgf8 double mutants recapitulated anterior mesoderm defects and Hh-dependent GLI transcription factors modulated enhancers at FGF gene loci. Cellular migration defects during gastrulation induced by Hh pathway antagonism were mitigated by FGF4 protein. These findings implicate a multicomponent signaling hierarchy activated by Hh ligands from the embryonic node and executed by FGF signals in nascent mesoderm to control anterior mesoderm patterning.
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Project description:Here, we report the generation of a new mouse model based on the Nmur1 promoter as a driver for simultaneous expression of Cre recombinase and green fluorescent protein (GFP), which allows gene targeting in ILC2 without affecting other innate and adaptive immune cells. By removing Id2 and Gata-3 using Cre-mediated gene deletion in Nmur1-expressing cells, we have generated mice with selective and specific deficiency in ILC2. ILC2-deficient mice have decreased eosinophil counts in steady state and are unable to recruit eosinophils in the airways in models of allergic asthma. Further, ILC2-deficient mice fail to mount an appropriate immune and epithelial type 2 response resulting in a profound defect in worm control and a non-protective type 3 immune response. In total, our data establish non-redundant functions for ILC2s in the presence of adaptive immune cells at steady state and during diseases and argue for a multilayered organization of the immune system based on a spatiotemporal division of labor.
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Project description:Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization. Canalization is essential for stabilizing cell fate, but mechanisms underlying robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state referred to as a saddle-node bifurcation. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of neurogenic factor POU3F1, preventing expression of neural suppressor REST, and disrupting composition of BRG1 complexes. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modeling supports all our observations. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1 mutant phenotypes, severely compromising cardiogenesis, unmasking an in vivo role for Brm. Our results reveal Brm as a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.
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Project description:Purpose: This study investigates the postnatal impact of Twist1 haploinsufficiency on the osteoskeletal ability and regeneration on two calvarial bones arising from tissues of different embryonic origin: the neural crest-derived frontal and the mesoderm-derived parietal bones. Results: Twist1 haplonsufficiency selectively enhanced osteogenic and tissue regeneration ability of mesoderm-derived parietal bones. Twist1 haplonsufficiency triggers its selective activity on mesoderm-derived parietal bone through downregulation of the bone-derived hormone Fgf23. Conclusions: Twist1 haploinsufficiency preferentially triggers osteogenic induction of parietal bones which may be beneficial to optimize treatments for skeletal regeneration, reconstruction and repair of mesoderm-derived bone, as well as to alleviate skeletal abnormalities caused by Twist1 haploinsufficiency.
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