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A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation.

Chemistry & biology | September 20, 2007 |

Saxe, Jonathan P | Wu, Hao | Kelly, Theresa K | Phelps, Michael E | Sun, Yi E | Kornblum, Harley I | Huang, Jing
Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Abstract

High-throughput identification of small molecules that selectively modulate molecular, cellular, or systems-level properties of the mammalian brain is ... his work highlights the tremendous potential of developing effective small-molecule drugs for use in regenerative medicine or transplantation therapy.

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.

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Nihms31166f1
Fig 1. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.
Nihms31166f1
Fig 1. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Fig 1

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Fig 2. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.
Nihms31166f2
Fig 2. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Fig 2

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Nihms31166f3
Fig 3. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.
Nihms31166f3
Fig 3. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Fig 3

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Nihms31166f4
Fig 4. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.
Nihms31166f4
Fig 4. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Fig 4

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Nihms31166f5
Fig 5. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.
Nihms31166f5
Fig 5. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Fig 5

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Fig 6. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.
Nihms31166f6
Fig 6. Saxe, Wu, et al. "A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation." Chemistry & biology 14.9 (2007): 1019-30. Web.

Fig 6

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