SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling

Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.

Le diable et l'artiste : la littérature et la peinture symbolistes en Russie

Le diable et l'artiste est une plongée dans l'atmosphère «démoniaque » qui régnait en Russie au passage du dix-neuvième au vingtième siècle. Au moment où la Russie, tout comme l'Europe, connaît un vif engouement pour l'ésotérisme, l'occultisme et la théosophie, les écrivains et les artistes s'emparent de la figure diabolique et l'adaptent à leur époque. Après le diable grandiose et solitaire de la période romantique, les symbolistes transforment et stylisent ce personnage, l'incarnant en de, multiples avatars, tantôt majestueux, tantôt petits et mesquins. Le sentiment apocalyptique qui imprègne le tournant du siècle, bientôt confirmé par les bouleversements socio-historiques, renforce encore le mysticisme des artistes et des écrivains, qui invoquent la présence du démon pour mieux comprendre le monde. Dans cet ouvrage, Fanny Mossière montre que la représentation symboliste du diable se caractérise par un «brouillage », un flou, une indétermination : toujours ambigu, insaisissable, «autre », le démon est difficile à percevoir. C'est le cas dans deux romans essentiels pour la période symboliste, L'ange de feu de Valerij Brjusov et Un démon de petite envergure de Fedor Sologub, qui mettent respectivement en scène le personnage mi-angélique mi-démoniaque de Madiel', et nedotykomka, démon informe et inquiétant. Le Maître et Marguerite de Mihail Bulgakov, plus tardif, s'inscrit dans la lignée du mouvement artistique et esthétique symboliste, tant au niveau stylistique que pour sa démonologie débridée. Enfin, une étude de l'oeuvre picturale de Mihail Vrubel', et plus particulièrement de son Démon, complète ce «portrait du diable » à l'orée du vingtième siècle.

Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C.

The corpus callosum (CC) is the main pathway responsible for interhemispheric communication. CC agenesis is associated with numerous human pathologies, suggesting that a range of developmental defects can result in abnormalities in this structure. Midline glial cells are known to play a role in CC development, but we here show that two transient populations of midline neurons also make major contributions to the formation of this commissure. We report that these two neuronal populations enter the CC midline prior to the arrival of callosal pioneer axons. Using a combination of mutant analysis and in vitro assays, we demonstrate that CC neurons are necessary for normal callosal axon navigation. They exert an attractive influence on callosal axons, in part via Semaphorin 3C and its receptor Neuropilin-1. By revealing a novel and essential role for these neuronal populations in the pathfinding of a major cerebral commissure, our study brings new perspectives to pathophysiological mechanisms altering CC formation.

B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.