Journal
CHEMISTRY & BIOLOGY
Volume 14, Issue 9, Pages 1019-1030Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2007.07.016
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Funding
- NATIONAL CANCER INSTITUTE [R01CA124974] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R21HG003729] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH065756] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA124974-01, R01 CA124974, R01 CA124974-03, R01 CA124974-02] Funding Source: Medline
- NHGRI NIH HHS [R21 HG003729-01A1, R21 HG003729, R21 HG003729-02] Funding Source: Medline
- NIMH NIH HHS [R01 MH65756] Funding Source: Medline
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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 (mGIuR4). siRNA-mediated knockdown of mGIuR4 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.
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