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Developmental Origin of the Cardiac Conduction System: Insight from Lineage Tracing

, University of Amsterdam , 1105 AZ Amsterdam , The Netherlands 1 Bastiaan J. Boukens 2 Rajiv A. Mohan 3 Vincent M. Christoffels The components of the cardiac conduction system (CCS) generate and propagate the

Structure and function of the Nppa–Nppb cluster locus during heart development and disease

Medical Center, University of Amsterdam , Meibergdreef 15, 1105 AZ Amsterdam , The Netherlands 1 Vincent M. Christoffels 2 Phil Barnett Atrial natriuretic factor and brain natriuretic peptide are two

GATA-dependent transcriptional and epigenetic control of cardiac lineage specification and differentiation

Heart progenitor cells differentiate into various cell types including pacemaker and working cardiomyocytes. Cell-type specific gene expression is achieved by combinatorial interactions between tissue-specific transcription factors (TFs), co-factors, and chromatin remodelers and DNA binding elements in regulatory regions. Dysfunction of these transcriptional networks may result...

Lack of Genetic Interaction between Tbx18 and Tbx2/Tbx20 in Mouse Epicardial Development

The epicardium, the outermost layer of the heart, is an essential source of cells and signals for the formation of the cardiac fibrous skeleton and the coronary vasculature, and for the maturation of the myocardium during embryonic development. The molecular factors that control epicardial mobilization and differentiation, and direct the epicardial-myocardial cross-talk are...

EMERGE: a flexible modelling framework to predict genomic regulatory elements from genomic signatures

Regulatory DNA elements, short genomic segments that regulate gene expression, have been implicated in developmental disorders and human disease. Despite this clinical urgency, only a small fraction of the regulatory DNA repertoire has been confirmed through reporter gene assays. The overall success rate of functional validation of candidate regulatory elements is low. Moreover...

Developing insights into cardiac regeneration

Vincent M. Christoffels ( William T. Pu we highlight some of the outstanding talks, advances and interesting questions from the meeting. t n e m p o l e v e D - Summary Owing to its intrinsic

Transcriptional Repressor Tbx3 Is Required for the Hormone-Sensing Cell Lineage in Mammary Epithelium

The transcriptional repressor Tbx3 is involved in lineage specification in several tissues during embryonic development. Germ-line mutations in the Tbx3 gene give rise to Ulnar-Mammary Syndrome (comprising reduced breast development) and Tbx3 is required for mammary epithelial cell identity in the embryo. Notably Tbx3 has been implicated in breast cancer, which develops in adult...

OccuPeak: ChIP-Seq Peak Calling Based on Internal Background Modelling

ChIP-seq has become a major tool for the genome-wide identification of transcription factor binding or histone modification sites. Most peak-calling algorithms require input control datasets to model the occurrence of background reads to account for local sequencing and GC bias. However, the GC-content of reads in Input-seq datasets deviates significantly from that in ChIP-seq...

Partial Absence of Pleuropericardial Membranes in Tbx18- and Wt1-Deficient Mice

The pleuropericardial membranes are fibro-serous walls that separate the pericardial and pleural cavities and anchor the heart inside the mediastinum. Partial or complete absence of pleuropericardial membranes is a rare human disease, the etiology of which is poorly understood. As an attempt to better understand these defects, we wished to analyze the cellular and molecular...

A novel fluorescent marker for molecular, structural and functional analysis of the cardiac conduction system

IntroductionThe function of the conduction system depends on structure, function and molecular composition of its components. Studying the relation between these aspects would greatly benefit from a mouse model in which the cells of the conduction system can be easily recognized in situ.MethodsWe generated a transgenic mouse model that expresses yellow fluorescent protein Venus...

Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of Gremlin1

Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient...

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. The underlying integration of patterning and cell cycle control during organogenesis is insufficiently understood. Here, we have investigated the function of the patterning T-box transcription factor gene Tbx2 in lung...

Identification and Functional Characterization of Cardiac Pacemaker Cells in Zebrafish

In the mammalian heart a conduction system of nodes and conducting cells generates and transduces the electrical signals evoking myocardial contractions. Specialized pacemaker cells initiating and controlling cardiac contraction rhythmicity are localized in an anatomically identifiable structure of myocardial origin, the sinus node. We previously showed that in mammalian embryos...

Identifying the Evolutionary Building Blocks of the Cardiac Conduction System

The endothermic state of mammals and birds requires high heart rates to accommodate the high rates of oxygen consumption. These high heart rates are driven by very similar conduction systems consisting of an atrioventricular node that slows the electrical impulse and a His-Purkinje system that efficiently activates the ventricular chambers. While ectothermic vertebrates have...

Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder and is characterized by abnormal development of the pharyngeal apparatus and heart. Cardiovascular malformations (CVMs) affecting the outflow tract (OFT) are frequently observed in 22q11.2DS and are among the most commonly occurring heart defects. The gene encoding T-box transcription factor 1...

The Ambiguous Role of NKX2-5 Mutations in Thyroid Dysgenesis

NKX2-5 is a homeodomain-containing transcription factor implied in both heart and thyroid development. Numerous mutations in NKX2-5 have been reported in individuals with congenital heart disease (CHD), but recently a select few have been associated with thyroid dysgenesis, among which the p.A119S variation. We sequenced NKX2-5 in 303 sporadic CHD patients and 38 families with at...

Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation

A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that...