Massé K , Dale N .

Wellcome Trust

	Fig. 1. Comparative embryogenesis of the mouse, chick, Xenopus and zebrafish. After fertilization (F), these four vertebrates undergo similar phases during their embryonic life. Species-specific stages are indicated on the figure. Briefly, Mouse embryos will implant (imp) at E4.5, after formation of the blastocyst and separation between the epiblast (or primitive ectoderm), at the origin of the embryo, and the cells which will give rise to the extra embryonic structures, the trophoectoderm and the primitive endoderm. The turning process, at E9, allows the establishment of the dorsal and ventral axis. The organogenesis is followed by the embryonic or foetal growth phase and birth takes place between 18 to 21 days after fertilization, depending on the mouse strain. The cleavage phase of the Chick embryos takes place in the hen oviduct. After laying, gastrulation and neurulation are complete in 2 days and stage HH14 is characterized by the existence of 22 somites. Feather germs appear at stage HH30 and organogenesis and embryo growth continue till hatching 22 days after fertilization. Cleavage of Xenopus embryos will be complete by stage 9, blastula stage and neurulation starts at stage 12.5 and ends at stage 20. First somite is formed at stage 17. Organogenesis is the longest phase, characterized by the hatching of the embryos from their vitelline membrane around stage 25. After stage 45, the tadpole will start feeding and will undergo the metamorphosis phase before becoming an adult frog. Zebrafish embryos display the quickest embryonic life cycle. Cleavage divisions lead to the formation of a blastoderm lying over the yolk, at the sphere stage, 4 h after fertilization. Gastrulation starts 5.5 h after fertilization, at the shield stage and is complete only 4.5 h later. Somite formation and neurulation follow during the segmentation period. Organogenesis then takes place during the pharyngula period, less than 24 h after fertilization, and zebrafish embryo usually hatches 48 to 72 h after fertilization. The term larva is being arbitrarily used after the end of the third day, whether the hatching has taken place or not
	Fig. 2. Temporal pattern of expression of the purinergic signalling components in mouse, chick, Xenopus and zebrafish embryos. The extent of expression of purinergic receptors and ectonucleotidases is mapped along the major phases of embryogenesis, cleavage, gastrulation, neurulation and organogenesis and embryo growth that have been normalized in duration for the four model organisms to allow easier comparison. The expression of some of these genes has only been described at one stage (indicated by arrows). EST expression data is indicated by blue dashed lines and corresponding gene names in blue. The expression of mouse genes published in [25] or [26] as part of the embryonic mouse database and atlas of gene expression are indicated by solid blue lines. The murine P2Y1 expression by in situ hybridization is available on the MGI website
	Fig. 3. Simulation of diffusion and metabolism of ATP—a complex purinergic morphogenetic field. The simulation (values shown at T = 5 s after beginning) shows that ATP and ADP are locally high in concentration over the first 30–40 μm, but that adenosine peaks at around 60 μm and remains high in concentration up to around 120 μm. Thus a complex pattern is produced where the potential for ATP/ADP actions is bounded and limited by a zone where adenosinergic actions have the potential to predominate. The simulation considers a short strip of cells (inset) where one cell at the end releases ATP; the ATP is then converted successively through the intervening intermediates to adenosine, with feed-forward inhibition of the final step mediated by ATP and ADP (inset top). All the metabolites diffuse along the strip with the same diffusion coefficient (300 μm2/s). The conversion of ATP and metabolites are described by Michaelis–Menten kinetics, based on literature values [93–95]: ATP, Km 33.3 μM, Vmax, 100 μM/s; ADP, Km 9.5 μM, Vmax 20 μM/s; AMP, Km 0.94 μM, Vmax, 20 μM/s; both ATP and ADP inhibit the conversion of AMP to adenosine (Ado) with a ki of 0.1 μM. The simulation is based on the following parallel linked equations: ∂[ATP]/∂t = D ∂2[ATP]/∂x2 − k1[ATP]; ∂[ADP]/∂t = D ∂2[ADP]/∂x2 + k1[ATP] − k2[ADP]; ∂[AMP]/∂t = D ∂2[AMP]/∂x2 + k2[ADP] − k3.ki[AMP]; and ∂[Ado]/∂t = D ∂2[Ado]/∂x2 + k3.ki[AMP]. Where D is the diffusion coefficient, and k1, k2 and k3 are rates based on the Michaelis–Menten kinetics given above. These equations were solved numerically using code written for Matlab. We thank Dr. Magnus Richardson for assisting us with this code

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