SALM1 controls synapse development by promoting F-actin/PIP2-dependent Neurexin clustering.

Synapse development requires spatiotemporally regulated recruitment of synaptic proteins. In this study, we describe a novel presynaptic mechanism of cis-regulated oligomerization of adhesion molecules that controls synaptogenesis. We identified synaptic adhesion-like molecule 1 (SALM1) as a constituent of the proposed presynaptic Munc18/CASK/Mint1/Lin7b organizer complex. SALM1 preferentially localized to presynaptic compartments of excitatory hippocampal neurons. SALM1 depletion in excitatory hippocampal primary neurons impaired Neurexin1ß- and Neuroligin1-mediated excitatory synaptogenesis and reduced synaptic vesicle clustering, synaptic transmission, and synaptic vesicle release. SALM1 promoted Neurexin1ß clustering in an F-actin- and PIP2-dependent manner. Two basic residues in SALM1's juxtamembrane polybasic domain are essential for this clustering. Together, these data show that SALM1 is a presynaptic organizer of synapse development by promoting F-actin/PIP2-dependent clustering of Neurexin.

Neural correlates of visual search in patients with hereditary retinal dystrophies.

In patients with central visual field scotomata a large part of visual cortex is not adequately stimulated. We investigated evidence for possible upregulation in cortical responses in 22 patients (8 females, 14 males; mean age 41.5 years, range 12-65 years) with central visual field loss due to hereditary retinal dystrophies (Stargardt's disease, other forms of hereditary macular dystrophies and cone-rod dystrophy) and compared their results to those of 22 age-matched controls (11 females, 11 males; mean age, 42.4 years, range, 13-70 years). Using functional magnetic resonance imaging (fMRI) we recorded differences in behavioral and BOLD signal distribution in retinotopic mapping and visual search tasks. Patients with an established preferred retinal locus (PRL) exhibited significantly higher activation in early visual cortex during the visual search task, especially on trials when the target stimuli fell in the vicinity of the PRL. Compared with those with less stable fixation, patients with stable eccentric fixation at the PRL exhibited greater performance levels and more brain activation.

Synapse associated protein 102 (SAP102) binds the C-terminal part of the scaffolding protein neurobeachin.

Neurobeachin (Nbea) is a multidomain scaffold protein abundant in the brain, where it is highly expressed during development. Nbea-null mice have severe defects in neuromuscular synaptic transmission resulting in lethal paralysis of the newborns. Recently, it became clear that Nbea is important also for the functioning of central synapses, where it is suggested to play a role in trafficking membrane proteins to both, the pre- and post-synaptic sites. So far, only few binding partners of Nbea have been found and the precise mechanism of their trafficking remains unclear. Here, we used mass spectrometry to identify SAP102, a MAGUK protein implicated in trafficking of the ionotropic glutamate AMPA- and NMDA-type receptors during synaptogenesis, as a novel Nbea interacting protein in mouse brain. Experiments in heterologous cells confirmed this interaction and revealed that SAP102 binds to the C-terminal part of Nbea that contains the DUF, PH, BEACH and WD40 domains. Furthermore, we discovered that introducing a mutation in Nbea's PH domain, which disrupts its interaction with the BEACH domain, abolishes this binding, thereby creating an excellent starting point to further investigate Nbea-SAP102 function in the central nervous system.

Database of Trypanosoma cruzi repeated genes: 20,000 additional gene variants.

BACKGROUND: Repeats are present in all genomes, and often have important functions. However, in large genome sequencing projects, many repetitive regions remain uncharacterized. The genome of the protozoan parasite Trypanosoma cruzi consists of more than 50% repeats. These repeats include surface molecule genes, and several other gene families. In the T. cruzi genome sequencing project, it was clear that not all copies of repetitive genes were present in the assembly, due to collapse of nearly identical repeats. However, at the time of publication of the T. cruzi genome, it was not clear to what extent this had occurred. RESULTS: We have developed a pipeline to estimate the genomic repeat content, where shotgun reads are aligned to the genomic sequence and the gene copy number is estimated using the average shotgun coverage. This method was applied to the genome of T. cruzi and copy numbers of all protein coding sequences and pseudogenes were estimated. The 22,640 results were stored in a database available online. 18% of all protein coding sequences and pseudogenes were estimated to exist in 14 or more copies in the T. cruzi CL Brener genome. The average coverage of the annotated protein coding sequences and pseudogenes indicate a total gene copy number, including allelic gene variants, of over 40,000. CONCLUSION: Our results indicate that the number of protein coding sequences and pseudogenes in the T. cruzi genome may be twice the previous estimate. We have constructed a database of the T. cruzi gene repeat data that is available as a resource to the community. The main purpose of the database is to enable biologists interested in repeated, unfinished regions to closely examine and resolve these regions themselves using all available shotgun data, instead of having to rely on annotated consensus sequences that often are erroneous and possibly misleading. Five repetitive genes were studied in more detail, in order to illustrate how the database can be used to analyze and extract information about gene repeats with different characteristics in Trypanosoma cruzi.