Global expression profiling reveals genetic programs underlying the developmental divergence between mouse and human embryogenesis

Abstract

Background: Mouse has served as an excellent model for studying human development and diseases due to its similarity to human. Advances in transgenic and knockout studies in mouse have dramatically strengthened the use of this model and significantly improved our understanding of gene function during development in the past few decades. More recently, global gene expression analyses have revealed novel features in early embryogenesis up to gastrulation stages and have indeed provided molecular evidence supporting the conservation in early development in human and mouse. On the other hand, little information is known about the gene regulatory networks governing the subsequent organogenesis. Importantly, mouse and human development diverges during organogenesis. For instance, the mouse embryo is born around the end of organogenesis while in human the subsequent fetal period of ongoing growth and maturation of most organs spans more than 2/3 of human embryogenesis. While two recent studies reported the gene expression profiles during human organogenesis, no global gene expression analysis had been done for mouse organogenesis.

Results: Here we report a detailed analysis of the global gene expression profiles from egg to the end of organogenesis in mouse. Our studies have revealed distinct temporal regulation patterns for genes belonging to different functional (Gene Ontology or GO) categories that support their roles during organogenesis. More importantly, comparative analyses identify both conserved and divergent gene regulation programs in mouse and human organogenesis, with the latter likely responsible for the developmental divergence between the two species, and further suggest a novel developmental strategy during vertebrate evolution.

Conclusions: We have reported here the first genome-wide gene expression analysis of the entire mouse embryogenesis and compared the transcriptome atlas during mouse and human embryogenesis. Given our earlier observation that genes function in a given process tends to be developmentally co-regulated during organogenesis, our microarray data here should help to identify genes associated with mouse development and/or infer the developmental functions of unknown genes. In addition, our study might be useful for invesgtigating the molecular basis of vertebrate evolution.

Figure 1

Morphological comparisons of mouse and human embryo development. Mouse embryonic stages (Theiler stages or TS) are based on somite number and characteristics [26]. There are 28 TS stages from the fertilization to birth, which is about 20 days post conception (dpc). Only 11 stages are shown. Human embryo stages were described by the Carnegie Institution of Washington, which are based on the developmental structures, not by size or the number of days of development [27]. The 23 Carnegie stages (CS) only covers the first 60 days of human embryo development, thereafter that the term embryo is replaced with fetus. 5 human embryos at 4-9^th week are shown here. The double headed arrows point to human and mouse embryos at similar stages of organogenesis.

Figure 2

Early embryogenesis involves many more regulated genes than late organogenesis during mouse development. The gene expression levels were compared between each pair of adjacent developmental stages to identify developmentally regulated genes. The total number of the genes regulated between the two stages (p < 0.01) were shown as a horizontal column (open and purple shaded columns). The number of genes whose expression levels were changed only between the two indicated stages, thus termed unique regulated genes, was shown as the purple shaded portion of the columns and its percentage in the total regulated genes was shown next to the column. Some enriched function categories (Gene Ontology or GO) for each group of uniquely regulated genes are shown on the right.

Figure 3

Different temporal regulation clusters are enriched with genes of distinct functional GO categories. The 11,458 regulated genes were divided into 20 clusters, Cluster I to XX (Additional file 3) (Additional file 4). Then the 20 clusters were divided into six groups referred to as group 1 to 6 (Additional file 4). One representative cluster from each of the six groups was shown here as Cluster I to VI, respectively. (A) Heat map (green to red: low to high levels of expression) showing the expression of the individual genes in Cluster I-VI. (B) Expression of the genes at different stages of development. Solid lines are drawn joining the average value of gene expression at each stage in the cluster. The dots reflect actual expression values. Some significantly enriched biological processes/categories for each cluster are shown in the grey box on the right.

Figure 4

Major temporal expression patterns during mouse organogenesis. (A)-(D) Genes that were significantly regulated during organogenesis (between stages TS13-TS27) were clustered and the four major patterns with genes that were gradually up-, down-, arch-down-, and arch-up-regulated are shown, respectively. (E)-(H) GO analysis were carried out on the genes belonging to the 4 clusters shown in A-D and the corresponding biological categories highly enrichments (p < 0.001) in each of the four gene patterns are shown in E-H, respectively. In addition, the tissues where these genes are preferentially expressed are also shown for each pattern (p < 0.001), indicating distinct tissue specificities.

Figure 5

Most of the up- and down-regulated genes are common during mouse and human organogenesis. (A) Venn diagrams between mouse and human genes whose expression significantly changed during organogenesis. (B-D) Venn diagrams of the subsets of genes in panel (A) that were up- (B), down- (C), and arch-up- (D) regulated, respectively. (E-G) Heat-map expression profiles of the common genes between human and mouse in B–D, respectively. (H-I) Heat-map expression profiles of selected genes involved in 4 signaling processes that are up- (H) or down- (I) regulated similarly during organogenesis in mouse and human.

Figure 6

A molecular interaction network during mouse organogenesis. (A) The 1000 most significantly regulated genes among the 4 major patterns shown in Figure 4 during mouse organogenesis were analyzed by using the STRING database to obtain a protein interaction network. Each line between any two proteins (dots) indicates an interaction. The genes are grouped into 4 categories based on their cellular locations. The color indicates the gene regulation patterns as in Figure 4. (B) The cell cycle sub-network showing that many interacting proteins have similar expression profiles: most genes on the left circle are down-regulated while those on the left are arch-up regulated. The size of each dot is proportional to the number of interactions the protein has within the network. (C) The neurogenesis genes subnetwork showing that the arch-down genes may function to bridge interactions among the proteins in different regulation groups in the network.