News tips from the Journal of Neuroscience

February 21, 2006

1. SALMs at the Synapses

Chang-Yu Wang, Kai Chang, Ronald S. Petralia, Ya-Xian Wang, Gail K. Seabold, and Robert J. Wenthold

Just when you thought you had memorized the names of all the synaptic proteins, along comes another family. This week, Wang et al. characterized a novel family of synaptic adhesion-like molecules (SALMs) 1-4. The postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 (PDZ) proteins help to organize the postsynaptic density. To look for novel interactors, the authors screened a mouse brain cDNA library in a yeast two-hybrid system using PDZ domains as bait. They identified SALM1 that, like several molecules involved in synapse formation, has extracellular IgG domains and intracellular PDZ-binding domains. The SALMs are related to the Nogo 66 receptor as well as the Slit and Amigo families. SALM1 bound to PSD-95 family members in heterologous cells and in rat brain. The SALMs enhanced surface expression and clustering of NMDA receptors via their PDZ-binding domain and interacted directly with NR1. Transfection of hippocampal neurons with SALM1 also increased neurite length in vitro.

2. Bigger and Better Synapses with SAP97

Maria Paz Regalado, Ryan T. Terry- Lorenzo, Clarissa L. Waites, Craig C. Garner, and Robert C. Malenka

In another look at synaptic structure in this week's Journal, Paz Regalado et al. hunted for postsynaptic density (PSD) proteins that could influence alignment with the presynaptic active zone through so-called retrograde or transynaptic signaling. The authors focused on membrane-associated guanylate kinase homologs (MAGUKs), a family of scaffold proteins including synapse-associated protein 97 (SAP97). When they overexpressed SAP97 in cultured hippocampal neurons, the protein appeared in dendritic puncta that colocalized with the presynaptic proteins synaptophysin, synapsin, and Bassoon. SAP97 expression increased the number of synapses, the level of staining of the proteins, and uptake of FM4-64. The effect of SAP97 involved protein binding to its PDZ (PSD-95/Discs large/zona occludens-1) domains of SAP97 as well as intact N-terminal and guanylate kinase domains. Studies with several inhibitors suggested a role for multiple cell adhesion molecules in signaling to the presynaptic compartment. Other MAGUKs, PSD-95 and SAP102, were less potent in these assays.

3. Male Behaviors and Sex Chromosome Genes

Jessica D. Gatewood, Aileen Wills, Savera Shetty, Jun Xu, Arthur P. Arnold, Paul S. Burgoyne, and Emilie F. Rissman

It's easy to blame testosterone for "male" behaviors such as aggression. But this week Gatewood et al. provide evidence suggesting that such behaviors depend on more than gonadal steroids. The authors used transgenic mice in which the testis-determining gene Sry on the Y chromosome, and thus the ultimate source of androgens, was uncoupled from other sex-linked genes. Sry was deleted from the Y chromosome and replaced by a transgenic copy on an autosomal chromosome. Thus groups of mice could be compared with or without Sry, and with or without the non-Sry sex chromosome genes. In tests of latency to aggression and in parenting behavior (pup retrieval) the sex chromosome complement, as well as gonadal steroids, influenced behavior. Although gonadal males, those with Sry with either the XX or XY- sex complement behaved similarly, other genes on the sex chromosome also played a role in these behaviors in gonadal females.

4. Probing Myelin Protein Zero Gain of Function Mutants

Lawrence Wrabetz, Maurizio D'Antonio, Maria Pennuto, Gabriele Dati, Elisa Tinelli, Pietro Fratta, Stefano Previtali, Daniele Imperiale, Jurgen Zielasek, Klaus Toyka, Robin L. Avila, Daniel A. Kirschner, Albee Messing, M. Laura Feltri, and Angelo Quattrini

The P0 glycoprotein is the most abundant protein in myelinated nerves. The extracellular immunoglobulin-like fold forms tetramers in trans that allow for the compaction of myelin layers. Although mutations in myelin protein zero [MPZ], P0) are well-known causes of neuropathy, the clinical phenotypes vary widely, in contrast to the mild abnormalities caused by heterozygous loss of function. Thus Wrabetz et al. explored the hypothesis that MPZ-neuropathies are attributable to gain of function mutations. They examined transgenic mice expressing MPZ mutations at S63, either S63del or S63C. S63del is the mutation underlying an adult-onset demyelinating neuropathy (Charcot-Marie-Tooth, Type 1B [CMT1B]), whereas the S63C mutation causes an early-onset demyelinating neuropathy Déjérine-Sottas syndrome). Both mutant alleles caused a demyelinating neuropathy despite the coexistence of normal alleles, consistent with a gain of function mechanism. S63C caused a packing defect in the myelin, whereas S63C was retained in the endoplasmic reticulum and elicited a presumably toxic unfolded protein response.
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Society for Neuroscience

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