An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers.
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.
Linhoff
Michael W
MW
The Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Laurén
Juha
J
Cassidy
Robert M
RM
Dobie
Frederick A
FA
Takahashi
Hideto
H
Nygaard
Haakon B
HB
Airaksinen
Matti S
MS
Strittmatter
Stephen M
SM
Craig
Ann Marie
AM
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology; D015723:Gene Library; D005820:Genetic Testing / Q000379:methods*; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology*; D054731:PDZ Domains / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D050598:Vesicular Glutamate Transport Protein 1; D051528:Guanylate Kinases