A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation.
High-throughput identification of small molecules that selectively modulate molecular, cellular, or systems-level properties of the mammalian brain is a significant challenge. Here we report the chemical genetic identification of the orphan ligand phosphoserine (P-Ser) as an enhancer of neurogenesis. P-Ser inhibits neural stem cell/progenitor proliferation and self-renewal, enhances neurogenic fate commitment, and improves neuronal survival. We further demonstrate that the effects of P-Ser are mediated by the group III metabotropic glutamate receptor 4 (mGluR4). siRNA-mediated knockdown of mGluR4 abolished the effects of P-Ser and increased neurosphere proliferation, at least in part through upregulation of mTOR pathway activity. We also found that P-Ser increases neurogenesis in human embryonic stem cell-derived neural progenitors. This work highlights the tremendous potential of developing effective small-molecule drugs for use in regenerative medicine or transplantation therapy.
Saxe
Jonathan P
JP
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Wu
Hao
H
Kelly
Theresa K
TK
Phelps
Michael E
ME
Sun
Yi E
YE
Kornblum
Harley I
HI
Huang
Jing
J
D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D009474:Neurons / Q000166:cytology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010768:Phosphoserine / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D010768:Phosphoserine; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; C108823:metabotropic glutamate receptor 4