Abstract
Development of appropriate dendritic arbors is crucial for neuronal information transfer. We show, using seizure-related gene 6 (sez-6) null mutant mice, that Sez-6 is required for normal dendritic arborization of cortical neurons. Deep-layer pyramidal neurons in the somatosensory cortex of sez-6 null mice exhibit an excess of short dendrites, and cultured cortical neurons lacking Sez-6 display excessive neurite branching. Overexpression of individual Sez-6 isoforms in knockout neurons reveals opposing actions of membrane-bound and secreted Sez-6 proteins, with membrane-bound Sez-6 exerting an antibranching effect under both basal and depolarizing conditions. Layer V pyramidal neurons in knockout brain slices show reduced excitatory postsynaptic responses and a reduced dendritic spine density, reflected by diminished punctate staining for postsynaptic density 95 (PSD-95). In behavioral tests, the sez-6 null mice display specific exploratory, motor, and cognitive deficits. In conclusion, cell-surface protein complexes involving Sez-6 help to sculpt the dendritic arbor, in turn enhancing synaptic connectivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Membrane / genetics
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Cell Membrane / metabolism
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Cells, Cultured
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Cerebral Cortex / abnormalities*
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Cerebral Cortex / cytology*
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Cerebral Cortex / metabolism
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Cognition Disorders / genetics
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Cognition Disorders / metabolism
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Cognition Disorders / physiopathology
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Dendrites / metabolism
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Dendrites / ultrastructure*
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Dendritic Spines / metabolism
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Dendritic Spines / ultrastructure
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Disks Large Homolog 4 Protein
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Excitatory Postsynaptic Potentials / genetics
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Female
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Gene Expression Regulation, Developmental / genetics*
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Guanylate Kinases
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / genetics*
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Nervous System Malformations / genetics
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Nervous System Malformations / metabolism
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Nervous System Malformations / physiopathology
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Neural Pathways / abnormalities
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Neural Pathways / cytology
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Neural Pathways / metabolism
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Organ Culture Techniques
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Patch-Clamp Techniques
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Pyramidal Cells / cytology*
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Pyramidal Cells / metabolism
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Synaptic Transmission / genetics
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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Sez6 protein, mouse
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Guanylate Kinases