Primary cilia control different steps of brain development

International audienceThe role of primary cilia in adult neurons remains elusive, however their developmental functions during brain morphogenesis have been recently highlighted thanks to mouse models. Unmistakably, they are needed for Hedgehog (Hh)-dependent patterning in the forebrain. Not only for Hh reception itself, but most importantly for a downstream event in the Hh transduction pathway, independent of Hh ligand: the Gli3 processing. Indeed, phenotypes due to cilia disruption in the developing brain, such as early patterning, olfactory bulb or corpus callosum formation, can be rescued by reintroducing Gli3-R (the short truncated form of Gli3 working as a transcriptional repressor of Hh target gene). In addition, primary cilia control the proliferation rate in different neural progenitors in the cortex, the hippocampus and the cerebellum; they are required for proper migration of interneurons. And cilia dysfunction is correlated with hydrocephaly, synaptogenesis defects and aberrant axonal tract projections. Most of these neurodevelopmental defects can be related to the various neurological features frequently observed across the ciliopathy spectrum. And thus, understanding the underlying mechanisms of these diverse functions of primary cilia in the brain is a new fundamental challenge

Eya, un activateur transcriptionnel à activité tyrosine-phosphatase

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Conserved rules in embryonic development of cortical interneurons

International audienceThis review will focus on early aspects of cortical interneurons (cIN) development from specification to migration and final positioning in the human cerebral cortex. These mechanisms have been largely studied in the mouse model, which provides unique possibilities of genetic analysis, essential to dissect the molecular and cellular events involved in cortical development. An important goal here is to discuss the conservation and the potential divergence of these mechanisms, with a particular interest for the situation in the human embryo. We will thus cover recent works, but also revisit older studies in the light of recent data to better understand the developmental mechanisms underlying cIN differentiation in human. Because cIN are implicated in severe developmental disorders, understanding the molecular and cellular mechanisms controlling their differentiation might clarify some causes and potential therapeutic approaches to these important clinical conditions

Redéploiement des gènes Six au cours de l’évolution

De l’oeil de drosophile au muscle de souris, l’histoire des gènes Six est intimement liée à celle des gènes Pax, Eya et Dach. Le premier membre de la famille, cloné chez la drosophile, a été baptisé sine oculis en raison de son rôle dans le développement oculaire, au cours duquel il agit en synergie avec les gènes eyeless (famille Pax), eyes absent (famille Eya) et dachshund (famille Dach). Des résultats récents semblent indiquer que les mécanismes décrits chez la drosophile ont été conservés au cours de l’évolution, pour la différenciation de l’oeil de vertébré, comme pour d’autres types de différenciation : Six1, notamment, semble être un acteur majeur de la myogenèse et participe au développement d’organes tels que les reins, le thymus ou l’oreille interne. Ces différentes fonctions sont à corréler avec la présence de partenaires Pax, Eya et Dach spécifiques dans les nombreux territoires d’expression du gène ; elles soulignent également l’importance de ces combinaisons de facteurs pendant l’organogenèse.It has become clear that during evolution, efficient molecular mechanisms are used over and over again to achieve various patterning tasks. The Six gene story illustrates a new aspect of the molecular conservation during embryogenesis. Members of the Six gene family have been identified on the basis of sequence homology with Drosophilasine oculis gene, which acts within a network of genes including eyeless (Pax family), eyes absent (Eya family) and dachshund (Dach family) to trigger compound eye organogenesis. Some aspects of the regulatory complex operating in Drosophila appear to be conserved during vertebrate eye patterning, but also for other differentiation processes. In this regard, Six1 is required nonetheless during myogenesis, but also for kidney, thymus, inner ear, nose, lacrimal and salivary gland organogenesis. These phenotypes are reminiscent of those previously described for Eya and Pax mutants, suggesting a functional link between these factors during mammalian organogenesis

Modifying transcript lengths of cycling mouse segmentation genes

International audienceSegmentation Transcriptional elongation Timing Oscillators Pattern formation A B S T R A C T Regular production of somites, precursors of the axial skeleton and attached muscles is controlled by a molecular oscillator, the segmentation clock, which drives cyclic transcription of target genes in the unsegmented presomitic mesoderm (PSM). The clock is based on a negative feedback loop which generates pulses of transcription that oscillate with the same periodicity as somite formation. Mutants in several oscillating genes including the Notch pathway gene Lunatic fringe (Lfng) and the Notch target Hes7, result in defective somitogen-esis and disorganised axial skeletons. Both genes encode negative regulators of Notch signalling output, but it is not yet clear if they are just secondary clock targets or if they encode components of a primary, pacemaker oscillator. In this paper, we try to identify components in the primary oscillator by manipulating delays in the feedback circuitry. We characterise recombinant mice in which Lfng and Hes7 introns are lengthened in order to delay mRNA production. Lengthening the third Hes7 intron by 10 or 20 kb disrupts accurate RNA splicing and inactivates the gene. Lfng expression and activity is normal in mice whose Lfng is lengthened by 10 kb, but no effects on segmentation are evident. We discuss these results in terms of the relative contributions of transcriptional and post-transcriptional delays towards defining the pace of segmenta-tion, and of alternative strategies for manipulating the period of the clock

Scalable asymmetric synthesis of a key fragment of Bcl-2/Bcl-xL inhibitors †

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Six homeoproteins directly activate Myod expression in the gene regulatory networks that control early myogenesis.

International audienceIn mammals, several genetic pathways have been characterized that govern engagement of multipotent embryonic progenitors into the myogenic program through the control of the key myogenic regulatory gene Myod. Here we demonstrate the involvement of Six homeoproteins. We first targeted into a Pax3 allele a sequence encoding a negative form of Six4 that binds DNA but cannot interact with essential Eya co-factors. The resulting embryos present hypoplasic skeletal muscles and impaired Myod activation in the trunk in the absence of Myf5/Mrf4. At the axial level, we further show that Myod is still expressed in compound Six1/Six4:Pax3 but not in Six1/Six4:Myf5 triple mutant embryos, demonstrating that Six1/4 participates in the Pax3-Myod genetic pathway. Myod expression and head myogenesis is preserved in Six1/Six4:Myf5 triple mutant embryos, illustrating that upstream regulators of Myod in different embryonic territories are distinct. We show that Myod regulatory regions are directly controlled by Six proteins and that, in the absence of Six1 and Six4, Six2 can compensate

Combining Phytoremediation and Biorefinery Strategies Assisted by an Ecofriendly Zwitterionic Ionic Liquid: A New Challenge for a Cleaner Bioeconomy

International audienceThis study aims to investigate the ability of an imidazolium biobased Zwitterionic Ionic Liquids (ZILs) in enhancing the phytoextraction of copper from garden and vineyard soils using the model plant ryegrass (Lolium perenne L.). The copper/ZIL molar ratio (1/4) introduced was rationally established based on molecular modeling and on the maximal copper concentration in artificially contaminated soil. Higher accumulation of copper in the shoots was detected for the uncontaminated and copper contaminated ZIL amended soils (18.9 and 23.3 mg.kg-1, respectively) together with a similar ZIL concentration of around 3% w/w detected by LC-MS analyses. These data evidenced a phytoextraction improvement of 38 and 66% compared to non-amended soils. ZIL would be mainly present under Cu(II)-ZIL4 complexes in the shoots. However depending on the soil modalities, the presence of free copper and/or free ZIL led to different chemical compositions in lignin and monomeric sugar contents. In the biorefinery context, performances of enzymatic hydrolysis of shoots were related to the presence of both ZIL and copper under free or complex forms. Ecotoxicity of the different soils indicated that the quantity of copper and ZIL remaining in the soils had no significant toxicity. ZIL amendment in a copper-contaminated soil was demonstrated as being a promising way to promote the valorization of phytoremediation plants

Copper-uptake mediated by an ecofriendly zwitterionic ionic liquid: A new challenge for a cleaner bioeconomy

This study aims to investigate the ability of an imidazolium biobased Zwitterionic Ionic Liquids (ZILs) in enhancing the phytoavailability of copper from garden (G) and vineyard (V) soils using the model plant ryegrass. Uncontaminated and artificially contaminated CuSO4 soils, unamended and ZIL-amended soil modalities were designed. The copper/ZIL mo-lar ratio (1/4) introduced was rationally established based on molecular modeling and on the maximal copper concentration in artificially contaminated soil. Higher accumulation of copper in the shoots was detected for the uncontaminated and copper contaminated ZIL amended V soils (18.9 and 23.3 mg/kg, respectively) contrary to G soils together with a ZIL concentration of around 3% (W/W) detected by LC-MS analyses. These data evidenced a Cu-accumulation improvement of 38% and 66% compared to non-amended V soils (13.6 and 13.9 mg/kg respectively). ZIL would be mainly present under Cu(II)-ZIL4 complexes in the shoots. The impact on the chemical composition of shoot was also studied. The results show that depending on the soils modalitity, the presence of free copper and/or ZIL led to different chemical compositions in lignin and monomeric sugar contents. In the biorefinery context, performances of enzymatic hydrolysis of shoots were also related to the presence of both ZIL and copper under free or complex forms. Ecotoxicity assessment of the vineyard soil samples indicated that the quantity of copper and ZIL remaining in the soils had no sig-nificant toxicity. ZIL amendment in a copper-contaminated soil was demonstrated as being a promising way to promote the valorization of phytoremediation plants

Six1 and Eya1 Expression Can Reprogram Adult Muscle from the Slow-Twitch Phenotype into the Fast-Twitch Phenotype

Muscle fibers show great differences in their contractile and metabolic properties. This diversity enables skeletal muscles to fulfill and adapt to different tasks. In this report, we show that the Six/Eya pathway is implicated in the establishment and maintenance of the fast-twitch skeletal muscle phenotype. We demonstrate that the MEF3/Six DNA binding element present in the aldolase A pM promoter mediates the high level of activation of this promoter in fast-twitch glycolytic (but not in slow-twitch) muscle fibers. We also show that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 proteins accumulate preferentially in the nuclei of fast-twitch muscles. The forced expression of Six1 and Eya1 together in the slow-twitch soleus muscle induced a fiber-type transition characterized by the replacement of myosin heavy chain I and IIA isoforms by the faster IIB and/or IIX isoforms, the activation of fast-twitch fiber-specific genes, and a switch toward glycolytic metabolism. Collectively, these data identify Six1 and Eya1 as the first transcriptional complex that is able to reprogram adult slow-twitch oxidative fibers toward a fast-twitch glycolytic phenotype