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Molecular and Cellular Biology
Article . 2010 . Peer-reviewed
License: ASM Journals Non-Commercial TDM
Data sources: Crossref
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Notch Exhibits Ligand Bias and Maneuvers Stage-Specific Steering of Neural Differentiation in Embryonic Stem Cells

Authors: Saravana Kumar, Ramasamy; Nibedita, Lenka;

Notch Exhibits Ligand Bias and Maneuvers Stage-Specific Steering of Neural Differentiation in Embryonic Stem Cells

Abstract

Notch dictates multiple developmental events, including stem cell maintenance and differentiation, through intercellular communication. However, its temporal influence during early development and, of particular interest, its regulation of binary fate decision at different stages during neurogenesis are among the least explored. Here, using an embryonic stem cell (ESC) model, we have deciphered Notch ligand preference during ESC commitment to different germ layers and determined the stage-specific temporal effect of Notch during neural differentiation. ESCs during maintenance remain impervious to Notch inhibition. However, Notch activation promotes differentiation even in the presence of leukemia inhibitory factor (LIF), displaying ligand preference-associated lineage discrimination, where Jagged-1 favors neural commitment and Delta-like-4 favors the mesoderm. This differential ligand action involves a combination of Notch receptors influencing specific downstream target gene expression. Though Notch activation during early neural differentiation specifically promotes neural stem cells or early neural progenitors and delays their maturation, its inhibition promotes late neural progenitors and expedites neurogenesis, with a preference for neurons over glia. However, gliogenesis is promoted upon Notch activation only when executed in combination with ciliary neurotrophic factor. Thus, our investigation underscores a multifaceted role of Notch, demonstrating the interdependency of ligand usage and lineage specification and Notch acting as a master switch, displaying stage-specific influence on neurogenesis.

Keywords

Homeodomain Proteins, Neurons, Receptors, Notch, Recombinant Fusion Proteins, Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Gene Expression Regulation, Developmental, Membrane Proteins, Cell Differentiation, Ligands, Leukemia Inhibitory Factor, Cell Line, Mice, Basic Helix-Loop-Helix Transcription Factors, Animals, Intercellular Signaling Peptides and Proteins, Cell Lineage, Neuroglia, Embryonic Stem Cells, Jagged-1 Protein

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    Top 10%
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    Top 10%
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    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
38
Top 10%
Top 10%
Top 10%
bronze
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