scholarly journals Opposing effects of Wnt/β-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea

Development ◽  
2021 ◽  
Vol 148 (11) ◽  
Author(s):  
Sara E. Billings ◽  
Nina M. Myers ◽  
Lee Quiruz ◽  
Alan G. Cheng
Keyword(s):  
Cell Fate ◽  
Mesenchymal Cell ◽  
Lateral Wall ◽  
Mesenchymal Cells ◽  
Sensory Cells ◽  
Dependent Manner ◽  
Cell Fates ◽  
Proliferation And Differentiation ◽  
A Cell ◽  
Opposing Effects

ABSTRACT During embryonic development, the otic epithelium and surrounding periotic mesenchymal cells originate from distinct lineages and coordinate to form the mammalian cochlea. Epithelial sensory precursors within the cochlear duct first undergo terminal mitosis before differentiating into sensory and non-sensory cells. In parallel, periotic mesenchymal cells differentiate to shape the lateral wall, modiolus and pericochlear spaces. Previously, Wnt activation was shown to promote proliferation and differentiation of both otic epithelial and mesenchymal cells. Here, we fate-mapped Wnt-responsive epithelial and mesenchymal cells in mice and found that Wnt activation resulted in opposing cell fates. In the post-mitotic cochlear epithelium, Wnt activation via β-catenin stabilization induced clusters of proliferative cells that dedifferentiated and lost epithelial characteristics. In contrast, Wnt-activated periotic mesenchyme formed ectopic pericochlear spaces and cell clusters showing a loss of mesenchymal and gain of epithelial features. Finally, clonal analyses via multi-colored fate-mapping showed that Wnt-activated epithelial cells proliferated and formed clonal colonies, whereas Wnt-activated mesenchymal cells assembled as aggregates of mitotically quiescent cells. Together, we show that Wnt activation drives transition between epithelial and mesenchymal states in a cell type-dependent manner.

scholarly journals p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner

PLoS ONE ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. e3707 ◽  
Author(s):  
Alina Molchadsky ◽  
Igor Shats ◽  
Naomi Goldfinger ◽  
Meirav Pevsner-Fischer ◽  
Melissa Olson ◽  
...  
Keyword(s):  
Cell Fate ◽  
Dependent Manner ◽  
Mesenchymal Differentiation ◽  
A Cell

scholarly journals Hypersensitivity to DNA damage leads to increased apoptosis during early mouse development

2000 ◽  
Vol 14 (16) ◽  
pp. 2072-2084
Author(s):  
Babette S. Heyer ◽  
Alasdair MacAuley ◽  
Ole Behrendtsen ◽  
Zena Werb
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Genotoxic Stress ◽  
Embryonic Cells ◽  
Mouse Development ◽  
Potential Cost ◽  
Proliferation And Differentiation ◽  
A Cell ◽  
Early Mouse ◽  
Surveillance Mechanism

Gastrulation in mice is associated with the start of extreme proliferation and differentiation. The potential cost to the embryo of a very rapid proliferation rate is a high production of damaged cells. We demonstrate a novel surveillance mechanism for the elimination of cells damaged by ionizing radiation during mouse gastrulation. During this restricted developmental window, the embryo becomes hypersensitive to DNA damage induced by low dose irradiation (<0.5 Gy) and undergoes apoptosis without cell cycle arrest. Intriguingly, embryonic cells, including germ cell progenitors, but not extraembryonic cells, become hypersensitive to genotoxic stress and undergo Atm- and p53-dependent apoptosis. Thus, hypersensitivity to apoptosis in the early mouse embryo is a cell fate-dependent mechanism to ensure genomic integrity during a period of extreme proliferation and differentiation.

scholarly journals Single-Cell RNA-seq Identifies Cell Diversity in Embryonic Salivary Glands

2019 ◽  
Vol 99 (1) ◽  
pp. 69-78 ◽  
Author(s):  
R. Sekiguchi ◽  
D. Martin ◽  
K.M. Yamada ◽  
Keyword(s):  
Epithelial Cells ◽  
Parotid Gland ◽  
Single Cell ◽  
Salivary Glands ◽  
Cell Fate ◽  
Mesenchymal Cell ◽  
Muscle Cells ◽  
Mesenchymal Cells ◽  
Organ Specificity ◽  
Bud Initiation

Branching organs, including the salivary and mammary glands, lung, and kidney, arise as epithelial buds that are morphologically very similar. However, the mesenchyme is known to guide epithelial morphogenesis and to help govern cell fate and eventual organ specificity. We performed single-cell transcriptome analyses of 14,441 cells from embryonic day 12 submandibular and parotid salivary glands to characterize their molecular identities during bud initiation. The mesenchymal cells were considerably more heterogeneous by clustering analysis than the epithelial cells. Nonetheless, distinct clusters were evident among even the epithelial cells, where unique molecular markers separated presumptive bud and duct cells. Mesenchymal cells formed separate, well-defined clusters specific to each gland. Neuronal and muscle cells of the 2 glands in particular showed different markers and localization patterns. Several gland-specific genes were characteristic of different rhombomeres. A muscle cluster was prominent in the parotid, which was not myoepithelial or vascular smooth muscle. Instead, the muscle cluster expressed genes that mediate skeletal muscle differentiation and function. Striated muscle was indeed found later in development surrounding the parotid gland. Distinct spatial localization patterns of neuronal and muscle cells in embryonic stages appear to foreshadow later differences in adult organ function. These findings demonstrate that the establishment of transcriptional identities emerges early in development, primarily in the mesenchyme of developing salivary glands. We present the first comprehensive description of molecular signatures that define specific cellular landmarks for the bud initiation stage, when the neural crest–derived ectomesenchyme predominates in the salivary mesenchyme that immediately surrounds the budding epithelium. We also provide the first transcriptome data for the largely understudied embryonic parotid gland as compared with the submandibular gland, focusing on the mesenchymal cell populations.

scholarly journals LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

2019 ◽  
Vol 5 (7) ◽  
pp. eaau5106 ◽  
Author(s):  
Anca G. Radu ◽  
Sakina Torch ◽  
Florence Fauvelle ◽  
Karin Pernet-Gallay ◽  
Anthony Lucas ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cell Fate ◽  
Neural Crest Cell ◽  
Dependent Manner ◽  
Cell Fates ◽  
Neural Crest Stem Cells ◽  
Metabolomic Profiling ◽  
Intestinal Pseudo Obstruction ◽  
Migratory Cells ◽  
Hind Limb Paralysis

Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.

scholarly journals Regardless of the deposition pathway, aminoacid 31 in histone variant H3 is essential at gastrulation in Xenopus

2019 ◽  
Author(s):  
David Sitbon ◽  
Ekaterina Boyarchuk ◽  
Geneviève Almouzni
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Unique Property ◽  
Dependent Manner ◽  
Critical Importance ◽  
Distinct Mode ◽  
Developmental Defects ◽  
A Cell ◽  
Cycle Dependent ◽  
Conserved Residue

AbstractThe closely related replicative H3 and non-replicative H3.3 variants show specific requirement during development in vertebrates. Whether it involves distinct mode of deposition or unique roles once incorporated into chromatin remains unclear. To disentangle the two aspects, we took advantage of the Xenopus early development combined with chromatin assays. Our previous work showed that in Xenopus, depletion of the non-replicative variant H3.3 impairs development at gastrulation, without compensation through provision of the replicative variant H3.2. We systematically mutated H3.3 at each four residues that differ from H3.2 and tested their ability to rescue developmental defects. Surprisingly, all H3.3 mutated variants functionally complemented endogenous H3.3, regardless of their incorporation pathways, except for one residue. This particular residue, the serine at position 31 in H3.3, gets phosphorylated onto chromatin in a cell cycle dependent manner. While the alanine substitution failed to rescue H3.3 depletion, a phosphomimic residue sufficed. We conclude that the time of gastrulation reveals a critical importance of the H3.3S31 residue independently of the variant incorporation pathway. We discuss how this single evolutionary conserved residue conveys a unique property for this variant in vertebrates during cell cycle and cell fate commitment.

scholarly journals Modeling binary and graded cone cell fate patterning in the mouse retina

2019 ◽  
Author(s):  
Kiara C. Eldred ◽  
Cameron Avelis ◽  
Robert J. Johnston ◽  
Elijah Roberts
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Cell Fate ◽  
Regulatory Network ◽  
Photoreceptor Cells ◽  
Mouse Retina ◽  
Hormone Signaling ◽  
Cell Fates ◽  
Opsin Expression ◽  
A Cell

AbstractNervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, M-opsin, or both S-opsin and M-opsin. These cell populations are patterned along the dorsal-ventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating M-opsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of ∼250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of S- and M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M- and S-opsin expression display differential, inverse patterns. Using these single-cell data we developed a quantitative, stochastic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates.Author SummaryThe development of a cell in a mammalian tissue is governed by a complex regulatory network that responds to many input signals to give the cell a distinct identity, a process referred to as cell-fate specification. Some of these cell fates have binary on-or-off gene expression patterns, while others have graded gene expression that changes across the tissue. Differentiation of the photoreceptor cells that sense light in the mouse retina provides a good example of this process. Here, we explore how complex patterns of cell fates are specified in the mouse retina by building a computational model based on analysis of a large number of photoreceptor cells from microscopy images of whole retinas. We use the data and the model to study what exactly it means for a cell to have a binary or graded cell fate and how these cell fates can be distinguished from each other. Our study shows how tens-of-thousands of individual photoreceptor cells can be patterned across a complex tissue by a regulatory network, creating a different outcome depending upon the received inputs.

scholarly journals Antibodies from combinatorial libraries use functional receptor pleiotropism to regulate cell fates

2015 ◽  
Vol 48 (4) ◽  
pp. 389-394 ◽  
Author(s):  
Richard A. Lerner ◽  
Rajesh K. Grover ◽  
Hongkai Zhang ◽  
Jia Xie ◽  
Kyung Ho Han ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Fate ◽  
Combinatorial Libraries ◽  
Animal Cells ◽  
Cell Fates ◽  
New Methods ◽  
A Cell ◽  
Functional Receptor

AbstractTo date, most antibodies from combinatorial libraries have been selected purely on the basis of binding. However, new methods now allow selection on the basis of function in animal cells. These selected agonist antibodies have given new insights into the important problem of signal transduction. Remarkably, when some antibodies bind to a given receptor they induce a cell fate that is different than that induced by the natural agonist to the same receptor. The fact that receptors can be functionally pleiotropic may yield new insights into the important problem of signal transduction.

Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis

Development ◽  
1995 ◽  
Vol 121 (1) ◽  
pp. 37-51 ◽  
Author(s):  
T.A. Mitsiadis ◽  
M. Salmivirta ◽  
T. Muramatsu ◽  
H. Muramatsu ◽  
H. Rauvala ◽  
...  
Keyword(s):  
Solid Phase ◽  
Biological Effects ◽  
Mesenchymal Cell ◽  
Basement Membranes ◽  
Dependent Manner ◽  
Heparin Binding ◽  
Limb Buds ◽  
New Family ◽  
A Cell

Midkine (MK) and heparin binding-growth associated molecule (HB-GAM or pleiotrophin), constitute a new family of heparin-binding proteins implicated in the regulation of growth and differentiation (T. Muramatsu (1993) Int. J. Dev. Biol. 37, 183–188). We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development. From 9 to 14.5 day post-coitum (dpc), both proteins were detected in central and peripheral nervous systems, facial processes, limb buds, sense organs, respiratory, digestive, urogenital, and skeletal systems. MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions. The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues. Our in situ hybridization results revealed a widespread expression of MK transcripts that was not always consistent with the distribution of MK protein in developing tissues. In many epithelio-mesenchymal organs MK and HB-GAM were codistributed with syndecan-1, a cell surface proteoglycan. In limb buds and facial processes, MK, HB-GAM, and syndecan-1 were localized to the apical epithelium and the adjacent proliferating mesenchyme. Both MK and HB-GAM bound syndecan-1 in solid-phase assays in a heparan sulfate-dependent manner. The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins. Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression. Taken together these results indicate that MK and HB-GAM may play regulatory roles in differentiation and morphogenesis of the vertebrate embryo, particularly in epithelio-mesenchymal organs, and suggest molecular interactions with syndecan-1.

scholarly journals Nuclear iASPP determines cell fate by selectively inhibiting either p53 or NF-κB

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wenjie Ge ◽  
Yudong Wang ◽  
Shanliang Zheng ◽  
Dong Zhao ◽  
Xingwen Wang ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Response ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Functional Interaction ◽  
Signaling Systems ◽  
Optimal Outcomes ◽  
A Cell ◽  
Response To Stress ◽  
Biological Outcomes

Abstractp53 and NF-κBp65 are essential transcription factors (TFs) in the cellular response to stress. Two signaling systems can often be entwined together and generally produce opposing biological outcomes in a cell context-dependent manner. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) has the potential to inhibit both p53 and NF-κBp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-κBp65 activities. An iASPP(295–828) mutant, which is exclusively located in the nucleus and has been shown to be essential for its inhibitory effects on p53/NF-κBp65, was used to investigate the functional interaction between iASPP and the two TFs. The results showed that iASPP inhibits apoptosis under conditions when p53 is activated, while it can also elicit a proapoptotic effect when NF-κBp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-κBp65, but with a preference toward p53, thereby producing an antiapoptotic outcome when both TFs were simultaneously activated. This may be due to stronger binding between p53 and iASPP than NF-κBp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-κBp65 are modulated by iASPP. Despite being a well-known oncogene, iASPP may have a proapoptotic role, which will guide the development of iASPP-targeted therapies to reach optimal outcomes in the future.

scholarly journals Mesenchymal Cell Growth and Differentiation on a New Biocomposite Material: A Promising Model for Regeneration Therapy

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 458 ◽  
Author(s):  
Leslie Pomeraniec ◽  
Dafna Benayahu
Keyword(s):  
Fluorescein Isothiocyanate ◽  
Mesenchymal Cell ◽  
Biological Properties ◽  
Mesenchymal Cells ◽  
Nano Particles ◽  
Culture Dish ◽  
Tissue Culture Dish ◽  
Tissue Organization ◽  
Proliferation And Differentiation

Mesenchymal stem cells serve as the body’s reservoir for healing and tissue regeneration. In cases of severe tissue trauma where there is also a need for tissue organization, a scaffold may be of use to support the cells in the damaged tissue. Such a scaffold should be composed of a material that can biomimic the mechanical and biological properties of the target tissues in order to support autologous cell-adhesion, their proliferation, and differentiation. In this study, we developed and assayed a new biocomposite made of unique collagen fibers and alginate hydrogel that was assessed for the ability to support mesenchymal cell-proliferation and differentiation. Analysis over 11 weeks in vitro demonstrated that the scaffold was biocompatible and supports the cells viability and differentiation to produce tissue-like structures or become adipocyte under differentiation medium. When the biocomposite was enriched with nano particles (NPs), mesenchymal cells grew well after uptake of fluorescein isothiocyanate (FITC) labeled NPs, maintained their viability, migrated through the biocomposite, reached, and adhered to the tissue culture dish. These promising findings revealed that the scaffold supports the growth and differentiation of mesenchymal cells that demonstrate their full physiological function with no sign of material toxicity. The cells’ functionality performance indicates and suggests that the scaffold is suitable to be developed as a new medical device that has the potential to support regeneration and the production of functional tissue.

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