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Lineage analysis of ventricular trabeculations to decipher the role of Nkx2-5 in conduction system development / Rôle de Nkx2-5 dans le lignage des trabécules ventriculaires au cours de la formation du système de conductionChoquet, Caroline 13 July 2018 (has links)
La coordination des battements cardiaques est assurée par la propagation rapide de l’activité électrique dans le système de conduction ventriculaire (SCV). Etudier la formation du SCV est crucial pour comprendre l’origine des troubles de conduction de l’adulte. Au cours de l’embryogénèse le SCV est issu des trabécules, des projections myocardiques à la surface interne des ventricules. Les trabécules subissent une compaction avant la naissance qui est nécessaire à la maturation du myocarde. Des défauts au cours des étapes embryonnaires seraient en cause dans l’apparition d’une cardiomyopathie rare nommée Non-Compaction du Ventricule Gauche (LVNC). LVNC et troubles de conduction observés chez des patients et des souris mutantes sont associés au gène NKX2-5, qui code pour un facteur de transcription clé pour le développement du cœur.Mon premier objectif de thèse consiste à étudier le rôle de Nkx2-5 dans l’origine et l’évolution pathologique de la LVNC. Mon second objectif consiste à définir le rôle de Nkx2-5 au cours du développement trabéculaire et de la formation du SCV afin de comprendre l’origine de l’hypoplasie du SCV chez les souris Nkx2-5 hétérozygotes.Des systèmes génétiques complexes ont été utilisés pour induire la délétion de Nkx2-5 dans les trabécules à plusieurs étapes du développement et suivre le destin des trabécules afin d’établir la fenêtre de ségrégation du lignage conducteur. L’ensemble de mes résultats ont permis d’identifier les étapes clés du développement du SCV et un rôle majeur de Nkx2-5 afin de mieux appréhender les troubles de conduction. Enfin mes résultats ont mis en évidence une nouvelle cible potentielle pour des perspectives thérapeutiques. / The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls the spatiotemporal contraction of the ventricles. A better understanding of VCS development is crucial to comprehend the etiology of conduction disturbances observed in adults. During embryogenesis, the VCS originates from ventricular trabeculae that are myocardial protrusions in the lumen of the ventricles. Before birth, trabeculae undergo a compaction step required for maturation of the myocardial wall. Impairment of these developmental steps can lead to the apparition of a rare cardiomyopathy referred as Left Ventricular Non-Compaction (LVNC). LVNC and conduction defects have been observed in patients and mutant mice carrying mutations in NKX2-5, encoding a key transcriptional regulator of heart development.The first objective of my thesis is to decipher the involvement of Nkx2-5 in the origin and pathological evolution of the LVNC. The second objective is to decipher the temporal requirement of Nkx2-5 during trabecular morphogenesis and VCS development and to understand the origin of the VCS hypoplasia observed in Nkx2-5 heterozygous mice. Complex genetic technics were used to induce the deletion of Nkx2-5 in ventricular trabeculae at different developmental time points and to trace the fate of trabeculae and establish the temporal window of the conductive lineage segregation during development.Altogether, my results identify key steps in the VCS development, demonstrate a crucial role of Nkx2-5 and contribute to improve understanding of conduction defects. Interestingly, my results potentially identify new target cells for therapeutic intervention.
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Identification of putative targets of Nkx2-5 in Xenopus laevis using cross-species annotation and microarray gene expression analysisBreese, Marcus R. 29 February 2012 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / The heart is the first organ to form during development in vertebrates and Nkx2-5 is the first marker of cardiac specification. In Xenopus laevis, Nkx2-5 is essential for heart formation, but early targets of this homeodomain transcription factor have not been fully characterized. In order to discover potential early targets of Nkx2-5, synthetic Nkx2-5 mRNA was injected into eight-cell Xenopus laevis embryos and changes in gene expression measured using microarray analysis. While Xenopus laevis is a commonly used model organism for developmental studies, its genome remains poorly annotated. To compensate for this, a cross-species annotation database called CrossGene was constructed. CrossGene was created by exhaustively comparing UniGene transcripts from Homo sapiens, Mus musculus, Rattus norvegicus, Gallus gallus, Xenopus laevis, Danio rerio, Drosophila melanogaster, and Caenorhabditis elegans using the BLAST family of algorithms. Networks were then assembled by recursively combining reciprocal best matches into groups of orthologous genes. Gene ontology annotation from all organisms could then be applied to all members of the reciprocal group. In this way, the CrossGene database was used to augment the existing genomic annotation of Xenopus laevis. Combining cross-species annotation with differential gene expression analysis of Nkx2-5 overexpression led to the discovery of 99 potential targets of Nkx2-5.
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Requirements for Nr2f transcription factors in the maintenance of atrial myocardial identity in vertebratesMartin, Kendall 02 June 2023 (has links)
No description available.
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The diagnosis of Patent Foramen Ovale, its importance in migraine, and an insight into its genetic basisVelupandian, Uma Maheshwari January 2012 (has links)
Background: Patent Foramen Ovale (PFO), a remnant of the foetal circulation, is emerging as a new cause of disease. It has been found to be associated with cryptogenic stroke in young adults, peripheral arterial embolism and neurological decompression sickness in divers. The detection of PFO remains a diagnostic challenge; transoesophageal echocardiogram being currently considered the ‘gold standard’. The development of a non-invasive technique is crucial for the identification of a venous-to-arterial shunt (v-aCS) which may permit paradoxical embolism. Little is known about the genetic basis of PFO and our limited knowledge is based on animal studies and gene mutations detected in patients with other cardiac septal defects. Methods: Study 1: PFO Detection and Evaluation: This study was designed to evaluate transcranial Doppler (TCD), transthoracic echocardiogram (TTE) and transoesophageal echocardiogram (TOE) with administration of contrast via arm and femoral veins. We then developed a standardized protocol for PFO detection and quantification using TCD. Study 2: PFO and Migraine: The PFO detection protocol developed from the first study formed the diagnostic technique to detect v-aCS in an adequately powered matched case control study to explore the association between PFO and migraine. Study 3: The Genetic basis of PFO: This study was designed to explore the genetic basis of a PFO using a candidate gene approach. Results: Study 1 - PFO Detection Study: When compared with TOE with femoral vein contrast injection as the ‘gold standard’, TCD with arm vein contrast was 100% sensitive and 97.4% specific for detecting a PFO. We defined a PFO positive (+ve) study on TCD as > 15 microbubbles entering the cerebral circulation, on TCD following arm vein injection and >16 microbubbles with a femoral contrast injection. A ‘major’ PFO+ve v-aCS was defined as >35 microbubbles with arm vein injection or >90 microbubbles with femoral vein injection. We then developed a new diagnostic pathway for PFO detection in clinical practice. Study 2 - PFO Migraine study: A significant difference in prevalence of v-aCS between migraine with aura M+A) and their matched controls was demonstrated with adjusted OR=3.72 (1.48-9.38) p=0.005 for a PFO+ve v-aCS, and a highly significant difference between M+A and controls for a ‘major’ PFO+ve v-aCS with adjusted OR = 6.38 (1.89 – 21.48) p = 0.003. There was significant association with APC resistance and migraine on thrombophilia screen. Study 3 - The PFO Genetics Study: This study detected mutations of GATA4 and NKX2-5 in both PFO+ve cases and PFO-ve controls. Two novel non synonymous mutations of GATA4, c.461T>A and c.994G>A were found only in PFO positive individuals and may be associated with a PFO. All the PFO+ve cases with a GATA4 gene mutation had a major PFO+ve v-aCSConclusion:TCD detects PFO with a sensitivity of 100% and specificity of 92.3% and is the most reliable non-invasive technique for PFO detection. When arm vein injections are used both cough and valsalva provocation is essential. There was a highly significant association between PFO+ve v- aCS and M+A, especially with a ‘major’ PFO+ve v-aCS. GATA 4 mutations though infrequent were found PFO+ve cases and all had major v-aCS.
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