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.

Understanding the transcriptional response to neuronal injury after trauma is a necessary prelude to formulation of therapeutic strategies. We used Serial Analysis of Gene Expression (SAGE) to identify 50,000 sequence tags representing 18,000 expressed genes in the cortex 2 h after traumatic brain injury (TBI). A similar tag library was obtained from sham-operated cortex. The SAGE data were validated on biological replicates using quantitative real-time-PCR on multiple samples at 2, 6, 12, and 24 h after TBI. This analysis revealed that the vast majority of genes showed a downward trend in their pattern of expression over 24 h. This was confirmed for a subset of genes using in situ hybridization and immunocytochemistry on brain sections. Of the overexpressed genes in the trauma library, Nedd4-WW (neural precursor cell expressed, developmentally downregulated) domain-binding protein 5 (N4WBP5) (also known as Ndfip1) is strongly expressed in surviving neurons around the site of injury. Overexpression of N4WBP5 in cultured cortical neurons increased the number of surviving neurons after gene transfection and growth factor starvation compared with control transfections. These results identify N4WBP5 as a neuroprotective protein and, based on its known interaction with the ubiquitin ligase Nedd4, would suggest protein ubiquitination as a possible survival strategy in neuronal injury.