Eugenio Medea Scientific Institute

Bosisio Parini, Italy

Eugenio Medea Scientific Institute

Bosisio Parini, Italy
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Guardiola O.,National Research Council Italy | Lafuste P.,Flemish Institute of Biotechnology | Lafuste P.,Catholic University of Leuven | Lafuste P.,University Paris Est Creteil | And 17 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. However, our understanding of the molecular mechanisms underlying satellite cell activation is still largely undefined. Here, we show that Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage. Conditional inactivation of cripto in adult satellite cells compromises skeletal muscle regeneration, whereas gain of function of Cripto accelerates regeneration, leading to muscle hypertrophy. Moreover, weprovide evidence that Criptomodulatesmyogenic cell determination and promotes proliferation by antagonizing the TGF-β ligand myostatin. Our data provide unique insights into the molecular and cellular basis of Cripto activity in skeletal muscle regeneration and raise previously undescribed implications for stem cell biology and regenerative medicine.


Pendin D.,Eugenio Medea Scientific Institute | Tosetto J.,Eugenio Medea Scientific Institute | Moss T.J.,Rice University | Andreazza C.,Eugenio Medea Scientific Institute | And 4 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

The mechanisms governing atlastin-mediated membrane fusion are unknown. Here we demonstrate that a three-helix bundle (3HB) within the middle domain is required for oligomerization. Mutation of core hydrophobic residues within these helices inactivates atlastin function by preventing membrane tethering and the subsequent fusion. GTP binding induces a conformational change that reorients the GTPase domain relative to the 3HB to permit self-association, but the ability to hydrolyze GTP is required for full fusion, indicating that nucleotide binding and hydrolysis play distinct roles. Oligomerization of atlastin stimulates its ability to hydrolyze GTP, and the energy released drives lipid bilayer merger. Mutations that prevent atlastin self-association also abolish oligomerization-dependent stimulation of GTPase activity. Furthermore, increasing the distance of atlastin complex formation from the membrane inhibits fusion, suggesting that this distance is crucial for atlastin to promote fusion.


Bertoletti E.,Vita-Salute San Raffaele University | Zanoni A.,Vita-Salute San Raffaele University | Giorda R.,Eugenio Medea Scientific Institute | Battaglia M.,Vita-Salute San Raffaele University
Developmental Cognitive Neuroscience | Year: 2012

Genetic variation of the A118G polymorphism of the μ-opioid receptor gene (OPRM1) predicts individual sensitivity to social rejection and fMRI activation during simulated social rejection in adults, while data on these relationships during childhood are lacking. We investigated whether this polymorphism predicts childhood withdrawal - a predictor of sensitivity to social rejection -, and the face-specific N170 event-related waveform in response to facial expressions. Among facial expressions, 'anger' was expected to be particularly evocative, as it communicates social rejection. Forty-nine children aged 8-10 years were characterised for their OPRM1 genotype, their score at the Withdrawn Scale of the Child Behavior Checklist (CBCL), and for N170 latencies and amplitudes recorded during a task of implicit processing of happy, neutral, and angry expressions of other children. Children carrying the OPRM1-G allele had higher CBCL Withdrawn scores and enhanced N170 amplitudes in response to facial expressions. Multiple linear regressions showed that the Withdrawn scale score predicts larger N170 amplitudes at the Pz and C4 electrodes, only for the anger expression. Children who carry one or two copies of the OPRM1 G-allele are more likely to manifest withdrawn behaviours, and differ for electrophysiological responses to the early phases of processing affective stimuli. © 2011 Elsevier Ltd. All rights reserved.


Tavano A.,Eugenio Medea Scientific Institute | Gagliardi C.,Eugenio Medea Scientific Institute | Martelli S.,Eugenio Medea Scientific Institute | Borgatti R.,Eugenio Medea Scientific Institute
Neuropsychologia | Year: 2010

The neurocognitive profile of Williams-Beuren syndrome (WBS) is characterized by visuospatial deficits, apparently fluent language, motor soft signs, and hypersociability. We investigated the association between neuromotor soft signs and visuospatial, executive-attentive, mnestic and linguistic functions in a group of 26 children and young adults with WBS. We hypothesized that neurological soft signs could be an index of subtle neurofunctional deficits and thus provide a behavioural window into the processes underlying neurocognition in Williams-Beuren syndrome. Dysmetria and dystonic movements were selected as grouping neurological variables, indexing cerebellar and basal ganglia dysfunction, respectively. No detrimental effects on visuospatial/visuoconstructive skills were evident following the presence of either neurological variable. As for language skills, participants with dysmetria showed markedly reduced expressive syntactic and lexico-semantic skills as compared to non-affected individuals, while no difference in chronological age was evident. Participants with dystonic movements showed reduced receptive syntax and increased lexical comprehension skills as compared to non-affected individuals, the age factor being significant. In both instances, the effect size was greater for syntactic measures. We take these novel findings as suggestive of a double dissociation between expressive and receptive skills at sentence level within the WBS linguistic phenotype. The investigation of neuromotor soft signs and neuropsychological functions may provide a key to new non-cortico-centric genotype/phenotype relationships. © 2010 Elsevier Ltd.


The research, which is featured in the April 1 issue of the Journal of Cell Science, is the first to show how the function of neurons is impaired by specific genetic defects that have been proven to cause HSP, a group of inherited neurological disorders that affect about 20,000 people in the United States. Those with HSP suffer from numbness and weakness in the legs and feet due to progressive deterioration of the neurons that carry signals from the brain to the spinal column, and Rice researchers hope that a better understanding of the root causes of HSP could lead to improved treatments. The new study is the latest to stem from a groundbreaking series of discoveries about HSP that have come from the laboratory of Rice biochemist James McNew since 2009. The new research was done in collaboration with the lab of fellow Rice biochemist Michael Stern and involved thousands of painstaking experiments by graduate students Jimmy Summerville, from Stern's group, and Joseph Faust, from McNew's. Summerville and Faust, co-lead authors of the new study, created dozens of mutant strains of the fruit fly Drosophila melanogaster, which has analogous genes to two human genes—atlastin and reticulon—that are known to cause HSP. By selectively mutating genes in the flies, Summerville and Faust manipulated the amount of the proteins atlastin and reticulon made in the flies' nerve cells. Both proteins are known to play roles in building and maintaining the structural framework of the endoplasmic reticulum (ER). The ER is an interconnected network of tubules and sheets that provide a cell with numerous critical functions. The research highlights the functional importance of the overall architecture and structure of the ER network. "This work is foundational in the sense that we now understand, at a mechanistic level, how ER structure influences the ability of a neuron to send a signal," McNew said. "That was unknown before. The ER is an essential organelle. Our cells need it to function correctly, and this study shows how a couple of specific changes to the ER can dramatically influence the ways that neurons 'talk' to muscles." HSP can be caused by defects in more than 70 genes, but defects to the atlastin gene have been linked to as many as 10 percent of HSP cases. Reticulon defects also can cause HSP, but the exact mechanisms by which these genes cause neurological problems are unclear. McNew began studying atlastin almost a decade ago, and in 2009 he and Italian scientist Andrea Daga of the Eugenio Medea Scientific Institute discovered that atlastin was a fusion protein that helped join together ER membranes. At the time, scientists knew that atlastin was associated with HSP, but its role as a membrane fusion protein was wholly unexpected because membrane fusion proteins were relatively rare and were all thought to operate in the same way. Scientists had never encountered a protein like atlastin, which is an enzyme that uses chemical energy to drive fusion. "Atlastin was completely different than any other membrane fusion protein, so we really had to start from scratch to determine how it worked," McNew said. Based on its role as a membrane fusion protein, McNew and colleagues hypothesized that atlastin was a key player in helping to form and maintain a healthy ER network in cells. Prior to the 2009 discovery, McNew's lab had used yeast as a model organism to study other fusion proteins. To study atlastin, he needed to adopt a new model organism, the fruit fly. As luck would have it, McNew's office in Rice's BioScience Research Collaborative was next door to Stern's, the leader of one of Rice's best-known groups for fruit fly research. The two researchers and their graduate students began collaborating, and McNew won a grant from the National Institutes of Health in 2011 to fund the experiments that Summerville and Faust carried out to study how atlastin influenced behavior at the cellular level. Stern said reticulon was thrown into the mix because it's also known to affect ER shape and structure, and because it sometimes counteracts atlastin. "One does one thing, and the other does another," he said. "They sort of work in opposition." Summerville and Faust first created three mutant strains of Drosophila: one that lacked the atlastin gene, another that lacked the reticulon gene and a third that lacked both genes. They then created dozens of subcategories of each type by adding back genes that would express one or more of the missing proteins in specific amounts and in specific tissues. They also created a new method for expressing a fluorescent tag in the ER so they could examine the resulting ER structure in Drosophila neuronal cells. In particular, they concentrated on the longest neurons in the flies' bodies, cells that stretched about 2 millimeters from end to end. These neurons are analogous to the human neurons that connect the spinal cord to the lower legs, which are immediately downstream of the corticospinal neurons that are known to misfunction in HSP patients. "These neurons are the longest cells in the human body," McNew said. "They can be up to a meter or more in length, and the hypothesis has long been that because these neurons are so long, they are somehow more susceptible to whatever ER defects result from the loss of atlastin or reticulon. "In fact, that is exactly what we found. Faust's imaging of the ER structure in the synapse found that the shape and look of the ER changed dramatically when atlastin was knocked out. Under normal conditions, the ER in the synapse forms a basket-like shape, and without atlastin, that structure is completely missing, and you just have diffuse ER material that is devoid of structure," McNew said. Stern said, "Even just seeing that there was a complex structure of ER within the nerve terminals was completely unknown before." Summerville's measurements of electrophysiological function also showed that neurons with these misshapen synapses released fewer neurotransmitters needed to activate attached muscles. The reticulon tests weren't as conclusive. While clear decreases in neuron function were observed when reticulon was absent, the team could not discern a visual difference in the ER structure when the protein was absent. Stern said the structural changes are so minute that they might only show up under a stronger microscope. Stern credited the success of the project to Summerville and Faust's determination and persistence. He said they had to improvise, in part because atlastin proved finicky to manipulate. "Normally, in a knockout study like this, you examine what happens in the negative case, where none of the protein is present, and then you make genetic manipulations to add back protein in specific tissues. This often leads to overexpression, where you have two or three or five times more protein than normal," Stern said. But this approach did not work for atlastin. Summerville found that even the slightest alterations in atlastin levels often caused the flies to die before they could be tested. "I think that's interesting scientifically," Stern said. "That says something about atlastin. But it also made Jimmy's life very difficult because it denied him the use of many of the tools that scientists take for granted when they do this type of study." While the new paper revealed some aspects of neuronal structure that had not yet been seen, Stern and McNew said they expect their follow-up study, which is already under way, to provide even more compelling results in terms of the mechanism by which HSP operates. "I view this paper as an introductory paper," Stern said. "We did the characterization that you need to do to get the foundation of what's going on. That turns this into science, and it sets the stage for the experiments that we're doing now, which are aimed at answering the question of what this protein is doing, not only in nervous system function, but also in terms of how it might be affecting the patients with this disease." Explore further: Little-known protein found to be key player More information: J. Summerville et al. The effects of ER morphology on synaptic structure and function in Drosophila melanogaster, Journal of Cell Science (2016). DOI: 10.1242/jcs.184929


Battaglia M.,Vita-Salute San Raffaele University | Battaglia M.,San Raffaele Hospital | Zanoni A.,Vita-Salute San Raffaele University | Taddei M.,Vita-Salute San Raffaele University | And 8 more authors.
Depression and Anxiety | Year: 2012

Background Cross-sectional studies report biased reactivity to facial expressions among shy children, anxious adolescents, and adults with social anxiety disorder (SAD). It remains unknown whether cerebral reactivity to facial expressions can predict longitudinally the development of SAD in adolescence and characterize the degree of social anxiety among the general population of adolescents. Methods In a longitudinal study of 21 general population volunteers characterized for behavioral and genetic variables, N400 event-related potentials, and 3-Tesla fMRI activations in response to happy/neutral/angry expressions were acquired at age 8-9 and 14-15, respectively. Results By stepwise regression, N400 amplitudes acquired at age 8-9 predicted the number of DSM-IV SAD symptoms at age 14-15, with the sole, significant (P =.018) contribution of the "anger" condition. Factorial ANOVA revealed increased (Voxel-Level P (FWE) range:.02-.0001) bilateral fMRI activations of several brain areas, including the amygdala, in response to facial expressions compared to a fixation cross. The number of symptoms of DSM-IV SAD was positively correlated with left amygdala response to angry (P (FWE) =.036) and neutral (P (FWE) =.025) facial expressions. Factorial ANOVA revealed that the 5-HTTLPR -S allele was associated with heightened left amygdala response to anger (P (FWE) =.05). Conclusion Cerebral reactivity to facial expressions, anger especially, measured at different developmental stages by different techniques is associated with adolescence SAD. The 5-HTTLPR genotype affects the neural processing of interpersonal affective stimuli during development. © 2011 Wiley-Liss, Inc.


Debattisti V.,Venetian Institute of Molecular Medicine | Pendin D.,Eugenio Medea Scientific Institute | Ziviani E.,University of Geneva | Daga A.,Eugenio Medea Scientific Institute | And 2 more authors.
Journal of Cell Biology | Year: 2014

Ablation of the mitochondrial fusion and endoplasmic reticulum (ER)-tethering protein Mfn2 causes ER stress, but whether this is just an epiphenomenon of mitochondrial dysfunction or a contributor to the phenotypes in mitofusin (Mfn)-depleted Drosophila melanogaster is unclear. In this paper, we show that reduction of ER dysfunction ameliorates the functional and developmental defects of flies lacking the single Mfn mitochondrial assembly regulatory factor (Marf). Ubiquitous or neuron- and muscle-specific Marf ablation was lethal, altering mitochondrial and ER morphology and triggering ER stress that was conversely absent in flies lacking the fusion protein optic atrophy 1. Expression of Mfn2 and ER stress reduction in flies lacking Marf corrected ER shape, attenuating the developmental and motor defects. Thus, ER stress is a targetable pathogenetic component of the phenotypes caused by Drosophila Mfn ablation. © 2014 Debattisti et al.


Bellani M.,University of Verona | Nobile M.,Eugenio Medea Scientific Institute | Bianchi V.,Eugenio Medea Scientific Institute | Van Os J.,Maastricht University | And 2 more authors.
Epidemiology and Psychiatric Sciences | Year: 2013

In a short series of articles, we will review the evidence for genotype by environment interaction (G × E) in developmental psychopathology. We will focus specifically on the characteristics of types of exposure assessed with respect to both their methods and findings. This article aims to review the studies exploring the moderating role of serotonin transporter on the effect of environmental adversities over time, particularly during childhood and adolescence, which is when level of internalizing symptoms and prevalence of mood disorders change substantially. Environmental adversities will not include abuse and maltreatment that have been reviewed before (see Bellani et al. 2012) and child's broader social ecology that will be reviewed in the next section. Copyright © Cambridge University Press 2012.


Romaniello R.,Eugenio Medea Scientific Institute | Tonelli A.,Eugenio Medea Scientific Institute | Arrigoni F.,Eugenio Medea Scientific Institute | Baschirotto C.,Eugenio Medea Scientific Institute | And 4 more authors.
Developmental Medicine and Child Neurology | Year: 2012

Neurological disorders characterized by abnormal neuronal migration, organization, axon guidance, and maintenance have recently been associated with missense and splice-site mutations in the genes encoding α- and β-tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. We found a novel heterozygous mutation c.419G>C in exon 4 of the gene encoding TUBB2B in a female with microcephaly, agenesis of the corpus callosum, open-lip schizencephaly of the left parietal lobe, extensive polymicrogyria, basal ganglia and thalami dysmorphisms, and vermis and right third nerve hypoplasia. The missense change results in a glycine to alanine substitution; the mutated residue falls within an invariant glycine-rich region and therefore is likely to result in impaired protein function and possibly microtubule formation. This study expands the spectrum of brain malformations associated with mutations in the β-tubulin gene TUBB2B, supporting its critical role in migration/organization and axon guidance processes. In addition, it suggests a possible genetic aetiology of schizencephaly, thus strengthening the hypothesis that there is a common pathophysiological base in polymicrogyria and schizencephaly. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.


Tavano A.,Eugenio Medea Scientific Institute | Borgatti R.,Eugenio Medea Scientific Institute
Cortex | Year: 2010

We compared the neurobehavioral profiles of children with Joubert syndrome (JS participants), a rare autosomal recessive condition characterized on magnetic resonance imaging (MRI) by hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations, and children with malformations confined to the cerebellar vermis and one or both hemispheres (Cerebellar malformations - CM participants). We aimed at investigating the influence of anatomo-clinical similarities (vermian malformation) and differences (intact cerebellar hemispheres vs sparing of the pons, respectively) with respect to cognitive, linguistic and emotional development, assuming as a reference framework the Cerebellar Cognitive Affective Syndrome (CCAS). Results show that severe to moderate mental retardation is infrequent in JS children, while it is present in more than half the sample of CM children. Affect development was generally preserved in JS, in high-functioning CM individuals and also in some of the CM children with moderate mental retardation, which raised questions as to the role of a cerebellar vermis lesion in determining affect disorders. Further, cognitive and linguistic profiles on both intellectual and neuropsychological evaluations provided evidence for distinct patterns of peaks and valleys in the two groups, with JS children being significantly more impaired in language and verbal working memory and CM individuals showing a significant impairment of executive functions and emotional development. The overall evidence provides support for an important role of cerebellar structures per se in shaping emotional, cognitive and linguistic development, when vermian lesions are associated to cerebellar hemispheric lesions. Cerebellar vermis and brainstem lesions instead appear to have a major impact on motor-related skills, including oro-motor abilities and verbal working memory. © 2009 Elsevier Srl.

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