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An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers.

Neuron | Mar 12, 2009

Delineating the molecular basis of synapse development is crucial for understanding brain function. Cocultures of neurons with transfected fibroblasts have demonstrated the synapse-promoting activity of candidate molecules. Here, we performed an unbiased expression screen for synaptogenic proteins in the coculture assay using custom-made cDNA libraries. Reisolation of NGL-3/LRRC4B and neuroligin-2 accounts for a minority of positive clones, indicating that current understanding of mammalian synaptogenic proteins is incomplete. We identify LRRTM1 as a transmembrane protein that induces presynaptic differentiation in contacting axons. All four LRRTM family members exhibit synaptogenic activity, LRRTMs localize to excitatory synapses, and artificially induced clustering of LRRTMs mediates postsynaptic differentiation. We generate LRRTM1(-/-) mice and reveal altered distribution of the vesicular glutamate transporter VGLUT1, confirming an in vivo synaptic function. These results suggest a prevalence of LRR domain proteins in trans-synaptic signaling and provide a cellular basis for the reported linkage of LRRTM1 to handedness and schizophrenia.

Pubmed ID: 19285470 RIS Download

Mesh terms: Animals | Cell Differentiation | Cells, Cultured | Cloning, Molecular | Cricetinae | Cricetulus | Embryo, Mammalian | Gene Expression | Gene Expression Regulation | Gene Library | Genetic Testing | Guanylate Kinases | Hippocampus | Humans | Intracellular Signaling Peptides and Proteins | Luminescent Proteins | Membrane Potentials | Membrane Proteins | Mice | Mice, Knockout | Neurons | PDZ Domains | Patch-Clamp Techniques | Presynaptic Terminals | Rats | Synapses | Transfection | Vesicular Glutamate Transport Protein 1

Data used in this publication

None found

Associated grants

  • Agency: NIMH NIH HHS, Id: R01 MH070860-03
  • Agency: NINDS NIH HHS, Id: NS 39962
  • Agency: NINDS NIH HHS, Id: R37 NS033020
  • Agency: NIMH NIH HHS, Id: R01 MH070860-01A1
  • Agency: NINDS NIH HHS, Id: R01 NS042304
  • Agency: NINDS NIH HHS, Id: R37 NS033020-17
  • Agency: NIMH NIH HHS, Id: R01 MH070860
  • Agency: NINDS NIH HHS, Id: NS 03220
  • Agency: NINDS NIH HHS, Id: R01 NS039962
  • Agency: NIMH NIH HHS, Id: R01 MH070860-04
  • Agency: NIMH NIH HHS, Id: R01 MH070860-02
  • Agency: NINDS NIH HHS, Id: R01 NS042304-08
  • Agency: NIMH NIH HHS, Id: MH 070860

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