Notch promotes neural lineage entry by pluripotent embryonic stem cells

Area of Science:

• Stem cell biology
• Developmental biology
• Cell signaling

Background:

• Embryonic stem cells (ESCs) differentiate asynchronously, with many adopting neural fates but others resisting or choosing non-neural paths.
• Cell-cell interactions appear to regulate this lineage commitment, as suggested by mosaic reporter gene activation.

Purpose of the Study:

• To investigate the role of the Notch signaling pathway in directing ESC lineage commitment.
• To determine if Notch signaling is conserved across different species of pluripotent stem cells.

Main Methods:

• Detected Notch receptors and ligands in mouse ESCs.
• Genetically manipulated Notch pathway activation (constitutive activation and interference).
• Utilized pharmacological inhibition of Notch signaling.
• Examined the interaction with fibroblast growth factor receptor (FGFR) signaling.
• Tested Notch ligand-expressing stromal cells on human ESCs.

Main Results:

• Constitutive Notch activation did not affect the ESC phenotype.
• Notch activation upon withdrawal of self-renewal stimuli directed differentiation exclusively into the neural lineage.
• Interference with Notch signaling suppressed neural fate choice.
• Notch-mediated neural commitment requires parallel signaling through FGFR.
• Notch ligands on stromal cells induced neural specification in human ESCs.

Conclusions:

• The Notch pathway plays a decisive role in directing ESCs towards the neural lineage.
• Notch signaling is a conserved mechanism for neural fate determination in pluripotent stem cells.
• Modulating Notch signaling is key to controlling ESC lineage choice and could overcome heterogeneous differentiation outcomes.