Abstract
Vertebrate embryos display a predominant head-to-tail body axis whose formation is associated with the progressive development of post-cranial structures from a pool of caudal undifferentiated cells. This involves the maintenance of active FGF signaling in this caudal region as a consequence of the restricted production of the secreted factor FGF8. FGF8 is transcribed specifically in the caudal precursor region and is down-regulated as cells differentiate and the embryo extends caudally. We are interested in understanding the progressive down-regulation of FGF8 and its coordination with the caudal movement of cells which is also known to be FGF-signaling dependent. Our study is performed using mathematical modeling and computer simulations. We use an individual-based hybrid model as well as a caricature continuous model for the simulation of experimental observations (ours and those known from the literature) in order to examine possible mechanisms that drive differentiation and cell movement during the axis elongation. Using these models we have identified a possible gene regulatory network involving self-repression of a caudal morphogen coupled to directional domain movement that may account for progressive down-regulation of FGF8 and conservation of the FGF8 domain of expression. Furthermore, we have shown that chemotaxis driven by molecules, such as FGF8 secreted in the stem zone, could underlie the migration of the caudal precursor zone and, therefore, embryonic axis extension. These mechanisms may also be at play in other developmental processes displaying a similar mode of axis extension coupled to cell differentiation.
Highlights
During embryonic development, generation of cell diversity needs to be coordinated with tissue growth in order to achieve the right size, cell number and shape of the different organs
We focus on the events that occur in the epiblast region that will give rise to the spinal cord as this is a tissue where the regulation of FGF8 transcription occurs but similar interactions may be relevant for mesoderm maturation
Based on our modeling and experimental results we suggest that the movement of the caudal precursor region is essential for the observed dynamics of the concentration patterns of involved morphogens, and that the interplay between these morphogens and the cells producing them is responsible for the progressive generation of differentiated cells as well as for the migration of the caudal neural precursor region (CNPR)
Summary
Generation of cell diversity needs to be coordinated with tissue growth in order to achieve the right size, cell number and shape of the different organs. Vertebrate embryos display very important differences along their rostro-caudal (head-to-tail) axis from very early stages of development which are manifested, for example, by the orientation and movement of the primitive streak along the rostro-caudal axis. This is a transient structure, composed of cells that form a groove in the epiblast, through which cells ingress to form the mesoderm and the endoderm. Primitive streak development goes through an initial phase of rostral elongation followed by caudal regression
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