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Regulation of early cardiopharyngeal fates specification

早期心咽命运规范的调节

基本信息

批准号：
9028926
负责人：
Lionel Christiaen
金额：
$ 39.03万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028926
关键词：
22q11.2 Address Biological Assay Biological Models Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Cycle Cell Lineage Cell division Cells Chordata Ciona intestinalis Confocal Microscopy Congenital Cardiovascular Abnormality Craniofacial Abnormalities Development DiGeorge Syndrome Diagnostic Embryo Embryonic Development Environment Event Face Facial Muscles Fibroblast Growth Factor Fluorescence-Activated Cell Sorting Future Gene Activation Gene Expression Gene Expression Profile Genetic Transcription Goals Hand Head Heart Heart Abnormalities Heart Atrium Inherited Jaw Knowledge Larva Lead Ligands Light Link MAP Kinase Gene Mammals Marine Invertebrates Mesenchyme Mesoderm Modeling Molecular Molecular Target Multipotent Stem Cells Mus Muscle Myocardium Pathway interactions Pattern Positioning Attribute Property Regulation Resolution Role Sampling Signal Transduction Source Specific qualifier value Stem cells Stereotyping Testing Therapeutic Tissues Vertebrates ascidian cardiogenesis dosage genome-wide heart cell innovation intercellular communication next generation novel pharynx muscle progenitor programs public health relevance research study response segregation spatiotemporal transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Modern diagnostics and treatments for inherited and acquired cardiovascular diseases require in-depth knowledge of the mechanisms that control heart cell identity during embryonic development. In mammals, the facial and lower jaw muscles - collectively referred to as pharyngeal muscles - share a common origin with heart progenitors in the cardiopharyngeal mesoderm. This relationship is reflected in the DiGeorge syndrome, where altered Tbx1 function causes cardiovascular and craniofacial malformations. The heart vs. pharyngeal muscle fate choice is difficult to study in the early mammalian embryos, as is the cellular environment, a.k.a. niche, which determines whether cardiopharyngeal progenitor cells remain multipotent or become specified into either cardiac or pharyngeal muscles. Larvae of the ascidian Ciona intestinalis, a marine invertebrate among the closest relatives to the vertebrates, possess a simplified cardiopharyngeal lineage of cells that make successive heart vs. pharyngeal muscles choices in a simple and stereotyped manner. This can be studied with high spatiotemporal resolution using targeted molecular perturbations, confocal microscopy and lineage- specific transcription profiling that combines fluorescence activated cell sorting (FACS) and next generation RNA sequencing (RNA-seq). The ascidian cardiopharyngeal mesoderm arises from two progenitors, which produce the heart and the atrial siphon muscles (ASM) that control the exhalant opening. It was found that bipotent cardiopharyngeal progenitors undergo oriented asymmetrical cell divisions that produce distinct first and second heart precursors and ASM precursors. Molecularly, the cardiopharyngeal progenitors display multilineage transcriptional priming, i.e. they activate both early cardiac and ASM programs. These then segregate to their corresponding precursors due to regulatory cross-antagonisms: early ASM regulators inhibit the heart program in ASM precursors, while the ASM program is inhibited in the heart precursors. Here, regulatory mechanisms governing progressive ASM fate specification will be analyzed by testing the hypothesis that feedforward regulatory circuits control sequential gene activation. Next, the hypothesis that the orientation of asymmetric cell division determines differential interaction between a specific niche and the ASM vs. heart precursors will be explored. Finally, defined tissue-specific molecular perturbations, FACS and RNA-seq assays, including from single-cell samples, will define transcriptional signatures for multipotent cardiopharyngeal progenitors, first and second heart precursors and early ASM precursors. These results will characterize the regulatory properties that define cardiopharyngeal multipotency and uncover mechanisms that regulate conserved heart vs. pharyngeal muscle fate choices in chordates.