Cell fate choices by Tbx1 in forming the mammalian heart
Tbx1 在形成哺乳动物心脏过程中的细胞命运选择
基本信息
- 批准号:10242828
- 负责人:
- 金额:$ 60.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-20 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:22q1122q11.23-DimensionalAPLN geneATAC-seqAffectAllelesAnteriorAortaBindingBinding ProteinsBinding SitesBiological ProcessCardiacCardiac developmentCell Differentiation processCell modelCellsChIP-seqChromatinChromosomesDataData SetDefectDiGeorge SyndromeEctopic ExpressionEmbryoEmbryonic DevelopmentFaceGene Expression ProfileGene ProteinsGeneral PopulationGenesGeneticGenetic TranscriptionHeartHeart AbnormalitiesHuman GeneticsImmunofluorescence ImmunologicIndividualLungMammalsMapsMesenchymeMesodermMesoderm CellMolecularMusMuscleMuscle FibersMutant Strains MiceMutationMyocardiumNeckNeonatalPathway interactionsPatientsPenetrancePersistent Truncus ArteriosusPharyngeal ApparatusPhenocopyPopulationPopulation SizesProcessRegulatory ElementRisk FactorsShprintzen syndromeTestingTimeTissuesbasecell behaviorcell typeconditional mutantcongenital heart disorderembryo tissueexperimental studyfunctional genomicsgastrulationinterestmouse modelmutantprecursor cellprogenitorprogramsreceptorsingle-cell RNA sequencingspatiotemporalstem cellstranscription factortranscriptomics
项目摘要
TBX1 encodes a T-box transcription factor required for cardiac development. This gene maps to
the chromosome 22q11.2 region that is deleted in patients with DiGeorge syndrome/velo-cardio-
facial syndrome or 22q11.2 deletion syndrome (22q11.2DS). Approximately 60% of 22q11.2DS
patients have congenital heart disease that mostly affects the cardiac outflow tract. A subset of
individuals with a mutation of the TBX1 gene but not a deletion has been identified and they
partially phenocopy patients with 22q11.2DS. Inactivation of one allele of Tbx1 in mice results in
mild defects, but inactivation of both alleles results in neonatal lethality with a persistent truncus
arteriosus, in which the aorta and pulmonary trunk fail to separate. This defect also occurs in 5-
10% of 22q11.2DS patients with congenital heart disease. To understand the function of Tbx1 in
mammals, we performed single cell RNA-sequencing (scRNA-seq) of cardiopharyngeal
mesoderm progenitor cells within the pharyngeal apparatus. We discovered a multilineage
progenitor (MLP) population that expresses genes important for forming the cardiac outflow tract
as well as branchiomeric muscles of the face and neck. The MLP population expands at the
expense of more differentiated populations when Tbx1 is inactivated in the cardiopharyngeal
mesoderm. Our main hypothesis is that Tbx1 is required in the MLP population for progression
towards more differentiated states needed for cardiac development. We propose three specific
aims to test this hypothesis. In the first aim, we will perform additional scRNA-seq experiments
and analyze the complete dataset to understand how the progression of MLP cells are altered in
Tbx1 conditional and global mutant mouse embryos. In Aim 2, we will determine where the MLP
cells are localized in the embryo. Preliminary data suggests that these cells are localized to the
nascent mesenchyme of the elongating pharyngeal apparatus. We will also inactivate Tbx1
specifically within the MLP cells to determine its particular functions. In Aim 3, we will turn to
functional genomic studies and will identify open and accessible chromatin for which harbors
TBX1 protein binding sites using ATAC-seq and ChIP-seq from embryo tissue. Preliminary data
suggests that we are able to identify direct transcriptional target genes. By these three aims, we
will understand the molecular functions of TBX1 in the progression of progenitor cells to more
differentiated states to build the cardiac outflow tract.
TBX1编码心脏发育所需的T-box转录因子。这个基因映射到
项目成果
期刊论文数量(0)
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{{ truncateString('BERNICE E MORROW', 18)}}的其他基金
Molecular pathogenesis of congenital heart disease mediated by neural crest and second heart field cells
神经嵴和第二心野细胞介导先天性心脏病的分子发病机制
- 批准号:
10621288 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome
22q11.2缺失综合征先天性心脏病的遗传修饰
- 批准号:
10373375 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome
22q11.2缺失综合征先天性心脏病的遗传修饰
- 批准号:
10553279 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Molecular pathogenesis of congenital heart disease mediated by neural crest and second heart field cells
神经嵴和第二心野细胞介导先天性心脏病的分子发病机制
- 批准号:
10435713 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Molecular and cellular mechanisms in cardiac outflow tract formation and defects
心脏流出道形成和缺陷的分子和细胞机制
- 批准号:
10289982 - 财政年份:2021
- 资助金额:
$ 60.56万 - 项目类别:
Molecular and cellular mechanisms in cardiac outflow tract formation and defects
心脏流出道形成和缺陷的分子和细胞机制
- 批准号:
10471433 - 财政年份:2021
- 资助金额:
$ 60.56万 - 项目类别:
Cell fate choices by Tbx1 in forming the mammalian heart
Tbx1 在形成哺乳动物心脏过程中的细胞命运选择
- 批准号:
10615781 - 财政年份:2020
- 资助金额:
$ 60.56万 - 项目类别:
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