title: The novel synaptogenic protein Farp1 links postsynaptic cytoskeletal dynamics and transsynaptic organization.
abstract: Synaptic adhesion organizes synapses, yet the signaling pathways that drive and integrate synapse development remain incompletely understood. We screened for regulators of these processes by proteomically analyzing synaptic membranes lacking the synaptogenic adhesion molecule SynCAM 1. This identified FERM, Rho/ArhGEF, and Pleckstrin domain protein 1 (Farp1) as strongly reduced in SynCAM 1 knockout mice. Farp1 regulates dendritic filopodial dynamics in immature neurons, indicating roles in synapse formation. Later in development, Farp1 is postsynaptic and its 4.1 protein/ezrin/radixin/moesin (FERM) domain binds SynCAM 1, assembling a synaptic complex. Farp1 increases synapse number and modulates spine morphology, and SynCAM 1 requires Farp1 for promoting spines. In turn, SynCAM 1 loss reduces the ability of Farp1 to elevate spine density. Mechanistically, Farp1 activates the GTPase Rac1 in spines downstream of SynCAM 1 clustering, and promotes F-actin assembly. Farp1 furthermore triggers a retrograde signal regulating active zone composition via SynCAM 1. These results reveal a postsynaptic signaling pathway that engages transsynaptic interactions to coordinate synapse development.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Cheadle
authors.forename: Thomas
authors.initials: T
authors.lastname: Biederer
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040901:Proteomics; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D000199:Actins; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C578332:FARP1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007136:Immunoglobulins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein