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A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell
Jonathan P Saxe1, Hao Wu, Theresa K Kelly
1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Chemistry & Biology
|September 22, 2007
Summary
Phosphoserine (P-Ser) enhances neurogenesis by inhibiting stem cell proliferation and promoting neuronal survival. Its effects are mediated by the mGluR4 receptor, offering potential for regenerative medicine.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Pharmacology
Background:
- Identifying small molecules to modulate brain function is challenging.
- Neurogenesis, the creation of new neurons, is crucial for brain health and repair.
- Targeting neurogenesis holds promise for regenerative medicine.
Purpose of the Study:
- To identify novel small molecules that enhance neurogenesis.
- To elucidate the molecular mechanisms underlying neurogenesis modulation.
- To explore the therapeutic potential of identified compounds.
Main Methods:
- Chemical genetic screening to identify neurogenesis enhancers.
- In vitro assays using neural stem cells and human embryonic stem cell-derived progenitors.
- siRNA-mediated knockdown to investigate receptor function.
- Analysis of signaling pathways, including mTOR.
Main Results:
- Phosphoserine (P-Ser) was identified as a novel enhancer of neurogenesis.
- P-Ser inhibits neural stem/progenitor cell proliferation and self-renewal.
- P-Ser promotes neurogenic fate commitment and enhances neuronal survival.
- The effects of P-Ser are mediated by group III metabotropic glutamate receptor 4 (mGluR4).
- mGluR4 knockdown abolished P-Ser effects and increased proliferation via mTOR pathway activation.
- P-Ser increased neurogenesis in human embryonic stem cell-derived neural progenitors.
Conclusions:
- Phosphoserine is a potent enhancer of neurogenesis with therapeutic potential.
- The mGluR4 receptor is a key mediator of P-Ser's pro-neurogenic effects.
- This discovery opens avenues for developing small-molecule drugs for regenerative medicine and transplantation therapies.
