10 research outputs found

    DMRT5, DMRT3, and EMX2 Cooperatively Repress at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors

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    Specification of dorsoventral regional identity in progenitors of the developing telencephalon is a first pivotal step in the development of the cerebral cortex and basal ganglia. Previously, we demonstrated that the two zinc finger doublesex and mab-3 related (Dmrt) genes, Dmrt5 (Dmrta2) and Dmrt3, which are coexpressed in high caudomedial to low rostrolateral gradients in the cerebral cortical primordium, are separately needed for normal formation of the cortical hem, hippocampus, and caudomedial neocortex. We have now addressed the role of Dmrt3 and Dmrt5 in controlling dorsoventral division of the telencephalon in mice of either sex by comparing the phenotypes of single knock-out (KO) with double KO embryos and by misexpressing Dmrt5 in the ventral telencephalon. We find that DMRT3 and DMRT5 act as critical regulators of progenitor cell dorsoventral identity by repressing ventralizing regulators. Early ventral fate transcriptional regulators expressed in the dorsal lateral ganglionic eminence, such as Gsx2, are upregulated in the dorsal telencephalon of Dmrt3;Dmrt5 double KO embryos and downregulated when ventral telencephalic progenitors express ectopic Dmrt5. Conditional overexpression of Dmrt5 throughout the telencephalon produces gene expression and structural defects that are highly consistent with reduced GSX2 activity. Further, Emx2;Dmrt5 double KO embryos show a phenotype similar to Dmrt3;Dmrt5 double KO embryos, and both DMRT3, DMRT5 and the homeobox transcription factor EMX2 bind to a ventral telencephalon-specific enhancer in the Gsx2 locus. Together, our findings uncover cooperative functions of DMRT3, DMRT5, and EMX2 in dividing dorsal from ventral in the telencephalon. SIGNIFICANCE STATEMENT We identified the DMRT3 and DMRT5 zinc finger transcription factors as novel regulators of dorsoventral patterning in the telencephalon. Our data indicate that they have overlapping functions and compensate for one another. The double, but not the single, knock-out produces a dorsal telencephalon that is ventralized, and olfactory bulb tissue takes over most remaining cortex. Conversely, overexpressing Dmrt5 throughout the telencephalon causes expanded expression of dorsal gene determinants and smaller olfactory bulbs. Furthermore, we show that the homeobox transcription factor EMX2 that is coexpressed with DMRT3 and DMRT5 in cortical progenitors cooperates with them to maintain dorsoventral patterning in the telencephalon. Our study suggests that DMRT3/5 function with EMX2 in positioning the pallial-subpallial boundary by antagonizing the ventral homeobox transcription factor GSX2

    Study of the role of transcription factors Dmrt3 and Dmrt5 during the cerebral cortex development in mouse

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    Le cortex cĂ©rĂ©bral est composĂ© d’un grand nombre de types de neurones organisĂ©s radialement en couches cellulaires et tangentiellement en aires corticales fonctionnellement distinctes. Son dĂ©veloppement est rĂ©gulĂ© par des signaux fonctionnant comme morphogĂšnes sĂ©crĂ©tĂ©s par des centres organisateurs situĂ©s Ă  la pĂ©riphĂ©rie du tĂ©lencĂ©phale dorsal. Ces morphogĂšnes contrĂŽlent l’expression dans les progĂ©niteurs corticaux de gĂšnes codant pour des facteurs de transcription qui rĂ©gulent la prolifĂ©ration, la diffĂ©renciation et la spĂ©cification des progĂ©niteurs corticaux. Les cascades de gĂšnes impliquĂ©es dans la mise en place du cortex cĂ©rĂ©bral dans lesquelles ces signaux et facteurs de transcription interviennent restent cependant actuellement mal connues.Les gĂšnes Dmrt3 et Dmrt5 appartiennent Ă  une famille de gĂšnes fortement conservĂ©e Ă©volutivement codant pour des facteurs de transcription Ă  doigt de zinc connus pour leur rĂŽle dans le dĂ©veloppement sexuel. Des rĂ©sultats obtenus dans le laboratoire ayant montrĂ© que Dmrt5 joue un rĂŽle crucial dans la neurogenĂšse au niveau du systĂšme olfactif chez le xĂ©nope, j’ai voulu savoir, dans un premier temps, si la fonction de Dmrt5 dans la neurogenĂšse Ă©tait une fonction ancestrale. Pour rĂ©pondre Ă  cette question, j’ai recherchĂ© des gĂšnes Dmrts chez une espĂšce de Cnidaire, Nematostella vectensis, et ai Ă©tudiĂ© leur expression au cours du dĂ©veloppement. L’un d’entre-eux, NvDmrtB, est fortement exprimĂ© dans le systĂšme nerveux et s’est avĂ©rĂ© ĂȘtre requis pour la diffĂ©renciation des cellules nerveuses chez N. vectensis, suggĂ©rant que les gĂšnes Dmrts avaient dĂ©jĂ  un rĂŽle dans la neurogenĂšse dans l’ancĂȘtre commun des BilatĂ©riens et des Cnidaires.Par ailleurs, d’autres travaux ont montrĂ© que chez la souris les gĂšnes Dmrt5 et Dmrt3 sont exprimĂ©s dans le cerveau en dĂ©veloppement au niveau du tĂ©lencĂ©phale dorsal. Afin d’approcher leur fonction dans le dĂ©veloppement cortical, j’ai analysĂ© leur expression au cours du dĂ©veloppement embryonnaire, caractĂ©risĂ© les anomalies de dĂ©veloppement du cortex cĂ©rĂ©bral des souris knockout Dmrt5-/- et Dmrt3-/- ainsi que des souris double knockout Dmrt3-/-;Dmrt5-/- et Ă©tudiĂ© leur rĂ©gulation. Mes rĂ©sultats ont montrĂ© que Dmrt3 et Dmrt5 sont coexprimĂ©s dans les progĂ©niteurs corticaux en gradient avec un maximum d’expression du cĂŽtĂ© caudo-mĂ©dian. J’ai Ă©galement observĂ© que l’absence de Dmrt5 induit une rĂ©duction de la taille des vĂ©sicules tĂ©lencĂ©phaliques et que les structures de la partie caudo-mĂ©diane du cortex telles que le plexus choroĂŻde et l’hippocampe sont altĂ©rĂ©es ainsi que les aires visuelle et somato-sensorielle. Au niveau molĂ©culaire, mes rĂ©sultats ont montrĂ© que Dmrt5 est requis pour l’expression de diffĂ©rents gĂšnes codant pour les signaux Wnt et Bmp sĂ©crĂ©tĂ©s au niveau de la rĂ©gion caudo-mĂ©diane des vĂ©sicules tĂ©lencĂ©phaliques, et qu’il contrĂŽle nĂ©gativement Pax6 et positivement Emx2, des dĂ©terminants respectivement de l’identitĂ© rostro-latĂ©rale et caudo-mĂ©diane du cortex cĂ©rĂ©bral. Bien que la taille des vĂ©sicules tĂ©lencĂ©phaliques n’apparaisse pas affectĂ©e chez les souris Dmrt3-/-, l’expression de diffĂ©rents composants de la voie Wnt et celle d'Emx2 et Pax6 est lĂ©gĂšrement altĂ©rĂ©e, comme chez les souris Dmrt5-/-. Chez les souris double knock-out Dmrt3-/-;Dmrt5-/-, une rĂ©duction de la taille du cortex et des altĂ©rations de l’expression des gĂšnes similaires et plus sĂ©vĂšres que celle des souris Dmrt5-/- ont Ă©tĂ© observĂ©es. Nous avons Ă©galement mis en Ă©vidence que l’expression de Dmrt3 est rĂ©duite chez les souris Dmrt5-/- et que inversement celle de Dmrt5 est lĂ©gĂšrement augmentĂ©e chez les souris Dmrt3-/-. Enfin, nous avons observĂ© que l’expression de ces deux gĂšnes est dĂ©pendante du facteur de transcription Gli3 et que seul l’expression de Dmrt3 requiert les facteurs de transcription Pax6 et Emx2.Ensemble, nos rĂ©sultats indiquent que les facteurs de transcription Dmrt5 et Dmrt3 contrĂŽlent le dĂ©veloppement de la partie caudo-mĂ©diane du cortex, Dmrt5 agissant en amont de Dmrt3. Ils suggĂšrent Ă©galement que ces facteurs y joueraient des rĂŽles partiellement redondants en rĂ©gulant l’expression de cibles communes tels les gĂšnes Wnt3a et Pax6.!Doctorat en sciences, SpĂ©cialisation biologie molĂ©culaireinfo:eu-repo/semantics/nonPublishe

    Study of the role of transcription factors Dmrt3 and Dmrt5 during the cerebral cortex development in mouse

    No full text
    Le cortex cĂ©rĂ©bral est composĂ© d’un grand nombre de types de neurones organisĂ©s radialement en couches cellulaires et tangentiellement en aires corticales fonctionnellement distinctes. Son dĂ©veloppement est rĂ©gulĂ© par des signaux fonctionnant comme morphogĂšnes sĂ©crĂ©tĂ©s par des centres organisateurs situĂ©s Ă  la pĂ©riphĂ©rie du tĂ©lencĂ©phale dorsal. Ces morphogĂšnes contrĂŽlent l’expression dans les progĂ©niteurs corticaux de gĂšnes codant pour des facteurs de transcription qui rĂ©gulent la prolifĂ©ration, la diffĂ©renciation et la spĂ©cification des progĂ©niteurs corticaux. Les cascades de gĂšnes impliquĂ©es dans la mise en place du cortex cĂ©rĂ©bral dans lesquelles ces signaux et facteurs de transcription interviennent restent cependant actuellement mal connues.Les gĂšnes Dmrt3 et Dmrt5 appartiennent Ă  une famille de gĂšnes fortement conservĂ©e Ă©volutivement codant pour des facteurs de transcription Ă  doigt de zinc connus pour leur rĂŽle dans le dĂ©veloppement sexuel. Des rĂ©sultats obtenus dans le laboratoire ayant montrĂ© que Dmrt5 joue un rĂŽle crucial dans la neurogenĂšse au niveau du systĂšme olfactif chez le xĂ©nope, j’ai voulu savoir, dans un premier temps, si la fonction de Dmrt5 dans la neurogenĂšse Ă©tait une fonction ancestrale. Pour rĂ©pondre Ă  cette question, j’ai recherchĂ© des gĂšnes Dmrts chez une espĂšce de Cnidaire, Nematostella vectensis, et ai Ă©tudiĂ© leur expression au cours du dĂ©veloppement. L’un d’entre-eux, NvDmrtB, est fortement exprimĂ© dans le systĂšme nerveux et s’est avĂ©rĂ© ĂȘtre requis pour la diffĂ©renciation des cellules nerveuses chez N. vectensis, suggĂ©rant que les gĂšnes Dmrts avaient dĂ©jĂ  un rĂŽle dans la neurogenĂšse dans l’ancĂȘtre commun des BilatĂ©riens et des Cnidaires.Par ailleurs, d’autres travaux ont montrĂ© que chez la souris les gĂšnes Dmrt5 et Dmrt3 sont exprimĂ©s dans le cerveau en dĂ©veloppement au niveau du tĂ©lencĂ©phale dorsal. Afin d’approcher leur fonction dans le dĂ©veloppement cortical, j’ai analysĂ© leur expression au cours du dĂ©veloppement embryonnaire, caractĂ©risĂ© les anomalies de dĂ©veloppement du cortex cĂ©rĂ©bral des souris knockout Dmrt5-/- et Dmrt3-/- ainsi que des souris double knockout Dmrt3-/-;Dmrt5-/- et Ă©tudiĂ© leur rĂ©gulation. Mes rĂ©sultats ont montrĂ© que Dmrt3 et Dmrt5 sont coexprimĂ©s dans les progĂ©niteurs corticaux en gradient avec un maximum d’expression du cĂŽtĂ© caudo-mĂ©dian. J’ai Ă©galement observĂ© que l’absence de Dmrt5 induit une rĂ©duction de la taille des vĂ©sicules tĂ©lencĂ©phaliques et que les structures de la partie caudo-mĂ©diane du cortex telles que le plexus choroĂŻde et l’hippocampe sont altĂ©rĂ©es ainsi que les aires visuelle et somato-sensorielle. Au niveau molĂ©culaire, mes rĂ©sultats ont montrĂ© que Dmrt5 est requis pour l’expression de diffĂ©rents gĂšnes codant pour les signaux Wnt et Bmp sĂ©crĂ©tĂ©s au niveau de la rĂ©gion caudo-mĂ©diane des vĂ©sicules tĂ©lencĂ©phaliques, et qu’il contrĂŽle nĂ©gativement Pax6 et positivement Emx2, des dĂ©terminants respectivement de l’identitĂ© rostro-latĂ©rale et caudo-mĂ©diane du cortex cĂ©rĂ©bral. Bien que la taille des vĂ©sicules tĂ©lencĂ©phaliques n’apparaisse pas affectĂ©e chez les souris Dmrt3-/-, l’expression de diffĂ©rents composants de la voie Wnt et celle d'Emx2 et Pax6 est lĂ©gĂšrement altĂ©rĂ©e, comme chez les souris Dmrt5-/-. Chez les souris double knock-out Dmrt3-/-;Dmrt5-/-, une rĂ©duction de la taille du cortex et des altĂ©rations de l’expression des gĂšnes similaires et plus sĂ©vĂšres que celle des souris Dmrt5-/- ont Ă©tĂ© observĂ©es. Nous avons Ă©galement mis en Ă©vidence que l’expression de Dmrt3 est rĂ©duite chez les souris Dmrt5-/- et que inversement celle de Dmrt5 est lĂ©gĂšrement augmentĂ©e chez les souris Dmrt3-/-. Enfin, nous avons observĂ© que l’expression de ces deux gĂšnes est dĂ©pendante du facteur de transcription Gli3 et que seul l’expression de Dmrt3 requiert les facteurs de transcription Pax6 et Emx2.Ensemble, nos rĂ©sultats indiquent que les facteurs de transcription Dmrt5 et Dmrt3 contrĂŽlent le dĂ©veloppement de la partie caudo-mĂ©diane du cortex, Dmrt5 agissant en amont de Dmrt3. Ils suggĂšrent Ă©galement que ces facteurs y joueraient des rĂŽles partiellement redondants en rĂ©gulant l’expression de cibles communes tels les gĂšnes Wnt3a et Pax6.!Doctorat en sciences, SpĂ©cialisation biologie molĂ©culaireinfo:eu-repo/semantics/nonPublishe

    The Xenopus doublesex-related gene Dmrt5 is required for olfactory placode neurogenesis.

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    The Dmrt (doublesex and mab-3 related transcription factor) genes encode a large family of evolutionarily conserved transcription factors whose function in sex specific differentiation has been well studied in all animal lineages. In vertebrates, their function is not restricted to the developing gonads. For example, Xenopus Dmrt4 is essential for neurogenesis in the olfactory system. Here we have isolated and characterized Xenopus Dmrt5 and found that it is coexpressed with Dmrt4 in the developing olfactory placodes. As Dmrt4, Dmrt5 is positively regulated in the ectoderm by neural inducers and negatively by proneural factors. Both Dmrt5 and Dmrt4 genes are also activated by the combined action of the transcription factor Otx2, broadly transcribed in the head ectoderm and of Notch signaling, activated in the anterior neural ridge. As for Dmrt4, knockdown of Dmrt5 impairs neurogenesis in the embryonic olfactory system and in neuralized animal caps. Conversely, its overexpression promotes neuronal differentiation in animal caps, a property that requires the conserved C-terminal DMA and DMB domains. We also found that the sea anenome Dmrt4/5 related gene NvDmrtb also induces neurogenesis in Xenopus animal caps and that conversely, its knockdown in Nematostella reduces elav-1 positive neurons. Together, our data identify Dmrt5 as a novel important regulator of neurogenesis whose function overlaps with that of Dmrt4 during Xenopus olfactory system development. They also suggest that Dmrt may have had a role in neurogenesis in the last common ancestor of cnidarians and bilaterians.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

    Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

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    The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2â€Čdeoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hyperm

    Economics and COVID-19: A Bibliometric Analysis of the First Months of Publications

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    This work discusses a bibliometric analysis of the papers published during 2020 about COVID-19 and three relevant economic keywords: GDP, unemployment, and innovation. Considering different outcomes, a significant diversity of journals without the focus on economic issues publishing articles discussing the economic impacts of the COVID-19 pandemic was observed. The authors have also suggested some correlated dimensions between the number of articles authored by researchers affiliated to different universities of diverse countries and the severity of the pandemic indicators observed for these spaces.info:eu-repo/semantics/publishedVersio

    The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals.

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    Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal-Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5(-/-) brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3(xt/xt) mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe

    Expanding roles for the evolutionarily conserved Dmrt sex transcriptional regulators during embryogenesis.

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    Dmrt genes encode a large family of transcription factors characterized by the presence of a DM domain, an unusual zinc finger DNA binding domain. While Dmrt genes are well known for their important role in sexual development in arthropodes, nematodes and vertebrates, several new findings indicate emerging functions of this gene family in other developmental processes. Here, we provide an overview of the evolution, structure and mechanisms of action of Dmrt genes. We summarize recent findings on their function in sexual regulation and discuss more extensively the role played by these proteins in somitogenesis and neural development.JOURNAL ARTICLESCOPUS: re.jinfo:eu-repo/semantics/publishe

    The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)

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    International audienceAbstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup

    Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study

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    International audienc
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