Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons

Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low‐affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin‐positive (PV) interneurons. Nrg3 and ErbB4 are located pre‐ and postsynaptically, respectively, in excitatory synapses on PV interneurons in vivo. Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short‐term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4⁺ interneurons and affects short‐term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non‐neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4⁺ interneurons.     

Effect of mitomycin C and bromodeoxyuridine on Fanconi anemia lymphocytes.

The authors studied the effect of mitomycin C (MMC) and bromodeoxyuridine (BrdU) on the induction of chromosome aberrations on lymphocytes of four patients with Fanconi anemia (FA) and of one normal subject. A control culture and six experiments were designed to test the possible synergic effect of MMC and BrdU. Their results revealed no evidence of MMC-BrdU synergism on the induction of chromosome aberrations in FA lymphocytes. However, chromosomes showed more damage when FA cells were harvested 24 h after MMC stress than when cells were harvested shortly after treatment. This can be explained by a DNA repair defect or by a toxic effect of oxygenation of cells during the procedure.     

Trisomy 9 mosaicism in a girl with multiple malformations

A one-year-old girl with a mosaicism for an extra chromosome 9 is reported. Clinical findings included severe growth and mental retardation, frequent respiratory infections, peculiar face, skeletal and craniofacial abnormalities, seizures, spasticity, cardiopulmonary, gastrointestinal and genitourinary alterations. These findings were compared to those of the 10 other previously reported cases of trisomy 9 mosaicism. This helps to define the most constant phenotypical characteristics and most frequent major malformations which occur in trisomy 9 mosaicism. It is noteworthy that the reported percentage of trisomic cells was different in lymphocytes and in fibroblasts in each case.     

The relationships of Gasteroclupea branisai Signeux, 1964, a freshwater double-armored herring (Clupeomorpha,Ellimmichthyiformes) from the Late Cretaceous-Paleocene of South America

The clupeomorph fish Gasteroclupea branisai Signeux, 1964 from the Late Cretaceous-Paleocene of El Molino Formation, Cayara locality, Bolivia is redescribed in detail. This South American double-armored herring is the sole member of the family Gasteroclupeidae and exhibits a unique combination of features (skull roof ornamented with fine tubercles, beryciform foramen, endopterygoid teeth, about 16–18 supraneurals, a series of 35–38 predorsal and 40 ventral scutes, median fins small and containing 12–14 rays) that clearly supports its assignment to the extinct clupeomorph order Ellimmichthyiformes. G. branisai shares a number of synapomorphies with Sorbinichthys elusivo and S. africanus (five hypurals, second hypural autogenous, distal end of the second uroneural not reaching the distal end of the first uroneural) with which it forms a monophyletic assemblage recognized herein for the first time as the new suborder Sorbinichthyoidei. The peculiar morphology of Gasteroclupea that is characterized by having an extremely deep abdominal profile, hypertrophied coracoid, and elongated pectoral fins, resembles in many aspects the body plan of extant freshwater hatchetfishes of the characiform family Gasteropelecidae, suggesting that the morphological adaptations of G. branisai can be related, at least in part, to a similar lifestyle.     

Evolutionary imprint of activation: The design principles of VSDs

Voltage-sensor domains (VSDs) are modular biomolecular machines that transduce electrical signals in cells through a highly conserved activation mechanism. Here, we investigate sequence–function relationships in VSDs with approaches from information theory and probabilistic modeling. Specifically, we collect over 6,600 unique VSD sequences from diverse, long-diverged phylogenetic lineages and relate the statistical properties of this ensemble to functional constraints imposed by evolution. The VSD is a helical bundle with helices labeled S1–S4. Surrounding conserved VSD residues such as the countercharges and the S2 phenylalanine, we discover sparse networks of coevolving residues. Additional networks are found lining the VSD lumen, tuning the local hydrophilicity. Notably, state-dependent contacts and the absence of coevolution between S4 and the rest of the bundle are imprints of the activation mechanism on the VSD sequence ensemble. These design principles rationalize existing experimental results and generate testable hypotheses.     

Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles

Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how GBA mutations influence pathogenesis, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. Accordingly, we hypothesized that GBA may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P, Drosophila homologue of mammalian p62, were reduced in muscle and brain tissue of Gba1b flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific GBA expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify Gba1b mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that Gba1b mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.