Coordination of synaptic adhesion with dendritic spine remodeling by AF-6 and kalirin-7.
Remodeling of central excitatory synapses is crucial for synapse maturation and plasticity, and contributes to neurodevelopmental and psychiatric disorders. Remodeling of dendritic spines and the associated synapses has been postulated to require the coordination of adhesion with spine morphology and stability; however, the molecular mechanisms that functionally link adhesion molecules with regulators of dendritic spine morphology are mostly unknown. Here, we report that spine size and N-cadherin content are tightly coordinated. In rat mature cortical pyramidal neurons, N-cadherin-dependent adhesion modulates the morphology of existing spines by recruiting the Rac1 guanine-nucleotide exchange factor kalirin-7 to synapses through the scaffolding protein AF-6/afadin. In pyramidal neurons, N-cadherin, AF-6, and kalirin-7 colocalize at synapses and participate in the same multiprotein complexes. N-cadherin clustering promotes the reciprocal interaction and recruitment of N-cadherin, AF-6, and kalirin-7, increasing the content of Rac1 and in spines and PAK (p21-activated kinase) phosphorylation. N-cadherin-dependent spine enlargement requires AF-6 and kalirin-7 function. Conversely, disruption of N-cadherin leads to thin, long spines, with reduced Rac1 contact, caused by uncoupling of N-cadherin, AF-6, and kalirin-7 from each other. By dynamically linking N-cadherin with a regulator of spine plasticity, this pathway allows synaptic adhesion molecules to rapidly coordinate spine remodeling associated with synapse maturation and plasticity. This study hence identifies a novel mechanism whereby cadherins, a major class of synaptic adhesion molecules, signal to the actin cytoskeleton to control the morphology of dendritic spines, and outlines a mechanism that underlies the coordination of synaptic adhesion with spine morphology.
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Zhong
Z
Xie
Huzefa
H
Photowala
Michael E
ME
Cahill
Deepak P
DP
Srivastava
Kevin M
KM
Woolfrey
Cassandra Y
CY
Shum
Richard L
RL
Huganir
Peter
P
Penzes
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015820:Cadherins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D060588:LIM Domain Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods
D000906:Antibodies; D015820:Cadherins; D000076122:Disks Large Homolog 4 Protein; D049452:Green Fluorescent Proteins; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018091:Receptors, AMPA; C507006:Afdn protein, rat; C501449:Dlg4 protein, rat; C102365:Kalrn protein, rat