Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons in mouse somatosensory cortex is activity dependent. We then investigated the relationship between activity, alternative splicing, and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation

Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities

The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly

Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.

Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations

L’âge du Fer en Basse-Normandie. Gestes funéraires en Gaule au Second-Âge du Fer. Volumes I et II

Cet ouvrage est la publication des actes du 33e colloque international de l’AFEAF, qui s’est tenu à Caen, du 20 au 24 mai 2009. De même que le colloque, il comprend deux parties. La première, qui contient dix-sept contributions, traite de l’actualité des recherches sur l’Âge du fer en Basse-Normandie, une région qui a connu un renouvellement important de la documentation permettant d’appréhender les dynamiques d’occupation et les formes d’organisation territoriale durant la Protohistoire. Plusieurs bilans synthétiques concernant l’habitat rural, les sites fortifiés et la culture matérielle, sont, entre autres, proposés ici. La seconde partie de l’ouvrage traite du thème de la mort et des pratiques funéraires durant la période Ve-Ier siècles avant J.-C. ; elle contient vingt-deux contributions. Ce sujet a été abordé en privilégiant quelques axes de réflexion, de façon à faciliter les comparaisons entre régions. À travers des bilans synthétiques, le thème spécialisé du colloque est traité à l’échelle de la Gaule, avec les éclairages de plusieurs régions de l’Europe celtique.This is the publication of the proceedings of the 33rd AFEAF symposium held in Caen from the 20th to the 24th of May 2009. Like the symposium, this book is divided in two parts. The first part, with its 17 contributions, deals with the current knowledge about the Iron Age in Lower Normandy. An important renewal of the documentation concerning this region allows a better understanding of the occupational processes and territorial organization existing throughout Protohistory. This first part also includes several summary reports on rural settlements, fortified sites as well as finds. The second part of the book, with 22 contributions, deals with the subject of death and funerary practices during the 5th to 1st centuries BC. The subject was discussed focussing on a chosen number of thoughts as to make it easier to compare between different regions. Various summary reports allow an overview of this specialized topic throughout Gaul with perspectives from other regions of Celtic Europe