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Notch promotes neural lineage entry by pluripotent embryonic stem cells.

TitleNotch promotes neural lineage entry by pluripotent embryonic stem cells.
Publication TypeJournal Article
Year of Publication2006
AuthorsLowell S, Benchoua A, Heavey B, Smith AG
JournalPLoS Biol
Volume4
Issue5
Paginatione121
Date Published2006 May
ISSN1545-7885
KeywordsAnimals, Cell Differentiation, Cell Lineage, Cells, Cultured, Embryonic Stem Cells, Gene Expression Regulation, Humans, Mice, Neurons, Phenotype, Pluripotent Stem Cells, Receptors, Notch, Signal Transduction
Abstract

A central challenge in embryonic stem (ES) cell biology is to understand how to impose direction on primary lineage commitment. In basal culture conditions, the majority of ES cells convert asynchronously into neural cells. However, many cells resist differentiation and others adopt nonneural fates. Mosaic activation of the neural reporter Sox-green fluorescent protein suggests regulation by cell-cell interactions. We detected expression of Notch receptors and ligands in mouse ES cells and investigated the role of this pathway. Genetic manipulation to activate Notch constitutively does not alter the stem cell phenotype. However, upon withdrawal of self-renewal stimuli, differentiation is directed rapidly and exclusively into the neural lineage. Conversely, pharmacological or genetic interference with Notch signalling suppresses the neural fate choice. Notch promotion of neural commitment requires parallel signalling through the fibroblast growth factor receptor. Stromal cells expressing Notch ligand stimulate neural specification of human ES cells, indicating that this is a conserved pathway in pluripotent stem cells. These findings define an unexpected and decisive role for Notch in ES cell fate determination. Limiting activation of endogenous Notch results in heterogeneous lineage commitment. Manipulation of Notch signalling is therefore likely to be a key factor in taking command of ES cell lineage choice.

DOI10.1371/journal.pbio.0040121
Alternate JournalPLoS Biol.
PubMed ID16594731
PubMed Central IDPMC1431581
Grant ListG0300058 / / Medical Research Council / United Kingdom
G9806702 / / Medical Research Council / United Kingdom