Serotonin transporter transgenic (SERTcre) mouse line reveals developmental targets of serotonin specific reuptake inhibitors (SSRIs)

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Developmental genetic bases behind the independent origin of the tympanic membrane in mammals and diapsids

International audienceThe amniote middle ear is a classical example of the evolutionary novelty. Although paleontological evidence supports the view that mammals and diapsids (modern reptiles and birds) independently acquired the middle ear after divergence from their common ancestor, the developmental bases of these transformations remain unknown. Here we show that lower-to-upper jaw transformation induced by inactivation of the Endothelin1-Dlx5/6 cascade involving Goosecoid results in loss of the tympanic membrane in mouse, but causes duplication of the tympanic membrane in chicken. Detailed anatomical analysis indicates that the relative positions of the primary jaw joint and first pharyngeal pouch led to the coupling of tympanic membrane formation with the lower jaw in mammals, but with the upper jaw in diapsids. We propose that differences in connection and release by various pharyngeal skeletal elements resulted in structural diversity, leading to the acquisition of the tympanic membrane in two distinct manners during amniote evolution

Vezatin is essential for dendritic spine morphogenesis and functional synaptic maturation.

International audienceVezatin is an integral membrane protein associated with cell-cell adhesion complex and actin cytoskeleton. It is expressed in the developing and mature mammalian brain, but its neuronal function is unknown. Here, we show that Vezatin localizes in spines in mature mouse hippocampal neurons and codistributes with PSD95, a major scaffolding protein of the excitatory postsynaptic density. Forebrain-specific conditional ablation of Vezatin induced anxiety-like behavior and impaired cued fear-conditioning memory response. Vezatin knock-down in cultured hippocampal neurons and Vezatin conditional knock-out in mice led to a significantly increased proportion of stubby spines and a reduced proportion of mature dendritic spines. PSD95 remained tethered to presynaptic terminals in Vezatin-deficient hippocampal neurons, suggesting that the reduced expression of Vezatin does not compromise the maintenance of synaptic connections. Accordingly, neither the amplitude nor the frequency of miniature EPSCs was affected in Vezatin-deficient hippocampal neurons. However, the AMPA/NMDA ratio of evoked EPSCs was reduced, suggesting impaired functional maturation of excitatory synapses. These results suggest a role of Vezatin in dendritic spine morphogenesis and functional synaptic maturation

Transitory expression of Dlx5 and Dlx6 in maxillary arch epithelial precursors is essential for upper jaw morphogenesis

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DLX Genes in the Development and Maintenance of the Vertebrate Skeleton: Implications for Human Pathologies

International audienceSkeletal shape and mechanical properties define, to a large extent, vertebrate morphology and physical capacities. During development, skeletal morphogenesis results from dynamic communications between chondrocytes, osteoblasts, osteoclasts, and other cellular components of the skeleton. Later in life, skeletal integrity depends on the regulatory cascades that assure the equilibrium between bone formation and resorption. Finally, during aging, skeletal catabolism prevails over anabolism resulting in progressive skeletal degradation. These cellular processes depend on the transcriptional cascades that control cell division and differentiation in each cell type. Most Distal-less (Dlx) homeobox transcription factors are directly involved in determining the proliferation and differentiation of chondrocytes and osteoblasts and, indirectly, of osteoclasts. While the involvement of Dlx genes in the regulation of skeletal formation has been well-analyzed thanks to several mutant mouse models, the role of these genes in the maintenance of bone integrity has been only partially studied. The importance of Dlx genes for adult bone tissues is evidenced by their central role in the regulatory pathways involving Osx/Sp7 and Runx2, the two major master genes of osteogenesis. Dlx genes appear to be involved in several bone pathologies including, for example, osteoporosis. Indeed, at least five large-scale GWAS studies which aimed to detect loci associated with human bone mineral density (BMD) have identified a known DLX5/6 regulatory region within chromosome 7q21.3 in proximity of SEM1/FLJ42280/DSS1 coding sequences, suggesting that DLX5/6 expression is critical in determining healthy BMD. This review aims to summarize the major findings concerning the involvement of Dlx genes in skeletal development and homeostasis and their involvement in skeletal aging and pathology

Approche génétique des mécanismes d’exocytose pendant le développement des circuits neuronaux

Les neurotransmetteurs ont été impliqués dans de nombreux processus neuro-développementaux. Les neurones en développement expriment les protéines du complexe SNARE, et les cônes de croissance contiennent de nombreuses vésicules suggérant un rôle de la fusion membranaire dans la croissance axonale. Cependant, à mesure que la machinerie moléculaire responsable de la fusion vésiculaire était révélée, les mutants des gènes codant pour ces protéines n’ont pas montré de défaut majeur d’organisation des projections neuronales. Ces protéines sont pourtant essentielles aux fonctions vitales de l’organisme. Pour étudier le rôle de ces gènes à des étapes plus tardives du développement des circuits neuronaux, nous avons analysé les cartes sensorielles tactiles et visuelles dont la construction est modulée par l’activité nerveuse. Les gènes Rim1 et Rim2 sont essentiels au couplage des canaux calciques et des complexes SNARE. La délétion de ces gènes n’abolit pas la libération constitutive de neuromédiateurs, mais empêche la libération synchrone, évoquée, de médiateurs en réponse à l’entrée de calcium. L’ablation spécifique des gènes Rim1/Rim2 a été ciblée dans les neurones de relais thalamiques, le cortex ou les cellules ganglionnaires de la rétine. Quand ces gènes sont délétés dans le thalamus, la différenciation corticale en barils est perturbée : les neurones post-synaptiques ne reçoivent pas les signaux appropriés pour leur différenciation morphologique et l’orientation de leurs dendrites. De manière plus surprenante, les neurones dépourvus d’une transmission synaptique normale sont cependant capables de s’organiser en cartes topographiques normales et forment des synapses matures correctement différenciées. Cependant, ces neurones se révèlent incapables d’établir une compétition appropriée dans les cibles neuronales. Ainsi les outils génétiques ciblant l’exocytose permettent de mieux définir les processus développementaux dépendant ou non de mécanismes synaptiques

Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants

Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr2B−/−), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr2B−/− mice. We find, here, that Htr2B−/− mice display an antidepressant-like phenotype, which includes reduced latency to feed in the novelty suppressed feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr2B+/+) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr2B−/− mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr2B−/− mice and similarly no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model displaying panoply of conditions among which behavioral, neurotrophic and plastic causative factors can be analyzed.Fil: Diaz, Silvina Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Narboux Nême, Nicolas. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Boutourlinsky, Katia. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Doly, Stéphane. Inserm; Francia. Universite Pierre et Marie Curie; FranciaFil: Maroteaux, Luc. Inserm; Francia. Universite Pierre et Marie Curie; Franci

Integration of H-2Z1, a Somatosensory Cortex-Expressed Transgene, Interferes with the Expression of the Satb1 and Tbc1d5 Flanking Genes and Affects the Differentiation of a Subset of Cortical Interneurons

International audienceH-2Z1 is an enhancer trap transgenic mouse line in which the lacZ reporter delineates the somatosensory area of the cerebral cortex where it is expressed in a subset of layer IV neurons. In the search of somatosensory specific genes or regulatory sequences, we mapped the H-2Z1 transgene insertion site to chromosome 17, 100 and 460 kb away from Tbc1d5 and Satb1 flanking genes. We show here that insertion of the H-2Z1 transgene results in three distinct outcomes. First, a genetic background-sensitive expression of lacZ in several brain and body structures. While four genes in a 1 Mb region around the insertion are expressed in the barrel cortex, H-2Z1 expression resembles more that of its two direct neighbors. Moreover, H-2Z1 closely reports most of the body and brain expression sites of the Satb1 chromatin remodeling gene including tooth buds, thymic epithelium, pontine nuclei, fastigial cerebellar nuclei, and cerebral cortex. Second, the H-2Z1 transgene causes insertional mutagenesis of Tbc1d5 and Satb1, leading to a strong decrease in their expressions. Finally, insertion of H-2Z1 affects the differentiation of a subset of cortical GABAergic interneurons, a possible consequence of downregulation of Satb1 expression. Thus, the H-2Z1 "somatosensory" transgene is inserted in the regulatory landscape of two genes highly expressed in the developing somatosensory cortex and reports for a subdomain of their expression profiles. Together, our data suggest that regulation of H-2Z1 expression results from local and remote genetic interactions