Dataset Information

Two different network topologies yield bistability in models of mesoderm and anterior mesendoderm specification in amphibians.

ABSTRACT: Understanding the Gene Regulatory Networks (GRNs) that underlie development is a major question for systems biology. The establishment of the germ layers is amongst the earliest events of development and has been characterised in numerous model systems. The establishment of the mesoderm is best characterised in the frog Xenopus laevis and has been well studied both experimentally and mathematically. However, the Xenopus network has significant differences from that in mouse and humans, including the presence of multiple copies of two key genes in the network, Mix and Nodal. The axolotl, a urodele amphibian, provides a model with all the benefits of amphibian embryology but crucially only a single Mix and Nodal gene required for the specification of the mesoderm. Remarkably, the number of genes within the network is not the only difference. The interaction between Mix and Brachyury, two transcription factors involved in the establishment of the endoderm and mesoderm respectively, is not conserved. While Mix represses Brachyury in Xenopus, it activates Brachyury in axolotl. Thus, whilst the topology of the networks in the two species differs, both are able to form mesoderm and endoderm in vivo. Based on current knowledge of the structure of the mesendoderm GRN we develop deterministic models that describe the time evolution of transcription factors in a single axolotl cell and compare numerical simulations with previous results from Xenopus. The models are shown to have stable steady states corresponding to mesoderm and anterior mesendoderm, with the in vitro model showing how the concentration of Activin can determine cell fate, while the in vivo model shows that ?-catenin concentration can determine cell fate. Moreover, our analysis suggests that additional components must be important in the axolotl network in the specification of the full range of tissues.

SUBMITTER: Brown LE

PROVIDER: S-EPMC4029075 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Two different network topologies yield bistability in models of mesoderm and anterior mesendoderm specification in amphibians.

Brown L E LE King J R JR Loose M M

Journal of theoretical biology 20140317

Understanding the Gene Regulatory Networks (GRNs) that underlie development is a major question for systems biology. The establishment of the germ layers is amongst the earliest events of development and has been characterised in numerous model systems. The establishment of the mesoderm is best characterised in the frog Xenopus laevis and has been well studied both experimentally and mathematically. However, the Xenopus network has significant differences from that in mouse and humans, including ...[more]

PMID: 24650939

Similar Datasets

Project description:The Dishevelled proteins transduce both canonical Wnt/β-catenin and non-canonical Wnt/planar cell polarity (PCP) signaling pathways to regulate many key developmental processes during embryogenesis. Here, we disrupt both canonical and non-canonical Wnt pathways by targeting the entire Dishevelled family of genes (Dvl1, Dvl2, and Dvl3) to investigate their functional roles in the early embryo. We identified several defects in anterior-posterior axis specification and mesoderm patterning in Dvl1+/-; Dvl2-/-; Dvl3-/- embryos. Homozygous deletions in all three Dvl genes (Dvl TKO) resulted in defects in distal visceral endoderm migration and a complete failure to induce mesoderm formation. To identify potential mechanisms that lead to the defects in the developmental processes preceding gastrulation, we generated Dvl TKO mouse embryonic stem cells (mESCs) and compared the transcriptional profile of these cells with wild-type (WT) mESCs during germ lineage differentiation into 3D embryoid bodies (EBs). While the Dvl TKO mESCs displayed similar morphology, self-renewal properties, and minor transcriptional variation from WT mESCs, we identified major transcriptional dysregulation in the Dvl TKO EBs during differentiation in a number of genes involved in anterior-posterior pattern specification, gastrulation induction, mesenchyme morphogenesis, and mesoderm-derived tissue development. The absence of the Dvls leads to specific down-regulation of BMP signaling genes. Furthermore, exogenous activation of canonical Wnt, BMP, and Nodal signaling all fail to rescue the mesodermal defects in the Dvl TKO EBs. Moreover, endoderm differentiation was promoted in the absence of mesoderm in the Dvl TKO EBs, while the suppression of ectoderm differentiation was delayed. Overall, we demonstrate that the Dvls are dispensable for maintaining self-renewal in mESCs but are critical during differentiation to regulate key developmental signaling pathways to promote proper axis specification and mesoderm formation.

Dataset Information

Two different network topologies yield bistability in models of mesoderm and anterior mesendoderm specification in amphibians.

Publications

Two different network topologies yield bistability in models of mesoderm and anterior mesendoderm specification in amphibians.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets