Abstract
Two types of distinct cardiac progenitor cell populations can be identified during early heart development: the first heart field (FHF) and second heart field (SHF) lineage that later form the mature heart. They can be characterized by differential expression of transcription and signaling factors. These regulatory factors influence each other forming a gene regulatory network. Here, we present a core gene regulatory network for early cardiac development based on published temporal and spatial expression data of genes and their interactions. This gene regulatory network was implemented in a Boolean computational model. Simulations reveal stable states within the network model, which correspond to the regulatory states of the FHF and the SHF lineages. Furthermore, we are able to reproduce the expected temporal expression patterns of early cardiac factors mimicking developmental progression. Additionally, simulations of knock-down experiments within our model resemble published phenotypes of mutant mice. Consequently, this gene regulatory network retraces the early steps and requirements of cardiogenic mesoderm determination in a way appropriate to enhance the understanding of heart development.
Highlights
The heart is the first functional organ to develop in mammals
The network is characterized by early signaling events during gastrulation resulting in cardiac specification and subsequent signaling activities at the cardiac crescent stage which separate the cardiac progenitor cell population into the territories of the first heart field (FHF) and the second heart field (SHF) lineages
Genes being specific for terminal differentiation such as myosin light chain genes (MLC) or myosin heavy chain genes (MHC) code for structural proteins and constitute the end of the developmental processes described by the regulatory network (Figure 1, FHF area)
Summary
After the end of gastrulation, cardiogenic progenitor cells constitute the cardiac crescent in the anterior mesoderm of the murine embryo At this stage the cardiogenic mesoderm splits from a common cardiovascular progenitor cell population [1,2] into two areas of differential gene expression: the so-called first heart field (FHF) and the second heart field (SHF). After mesoderm formation cardiogenic precursor cells are characterized by the expression of the transcription factor Mesp1 [6]. Endodermal signals such as Bmp were described as being crucial for cardiogenesis [7,8,9]. A deeper understanding of the cardiac gene regulatory network requires the implementation of this network as a computational model and its subsequent analysis by computational simulations
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