Antagonistic transcription factors control the development of different tissues from a pool of stem cells

Berlin scientists present a global analysis on how the development of different tissues of the trunk is controlled

September 20, 2017

During embryonic development, neural tissues such as the spinal cord, as well as mesodermal tissues of the trunk, e.g., the skeleton and skeletal muscles derive from a homogeneous group of neuro-mesodermal progenitor cells (NMPs). The development into neural or mesodermal tissue is controlled by the transcription factors Sox2 and Brachyury. However, the exact details of the control mechanism have been unclear. In a global analysis, scientists of the Department of Developmental Genetics at the Max Planck Institute for Molecular Genetics in Berlin have shown that Brachyury and Sox2 antagonize each other in determining the cell fate of the descendants of NMPs. The work provides a basis for the elucidation of disease processes and malformations resulting from dysfunction of these control mechanisms.

In order to build a complete organism from a fertilized egg cell (zygote), the egg cell and its descendants have to divide multiple times. The genome of the zygote is conserved in identical form in all daughter cells, but depending on their stage of development and their position in the growing organism, different cells need to activate or repress different sets of genes in order to form a specific tissue or organ. This is done with the aid of so-called transcription factors; proteins that can bind directly to the DNA of a cell and thereby turn specific sets of genes on or off.

During the first days of embryonic development, embryonic stem cells form an epithelial cell layer (epiblast), from which two more but different cell layers derive. These three cell layers, the so-called germ layers, give rise to all of an organism’s tissues and organs. The most exterior layer is called ectoderm; it differentiates to form e.g. the nervous system and the skin. The middle layer (mesoderm) forms for instance the muscles and the skeleton, while the innermost layer (endoderm) produces the gastrointestinal tract and other internal organs.

The development of an embryo starts with the formation of the head anlage. While the brain and head take shape, the trunk develops gradually by a continuous elongation of the body axis. The trunk arises out of a group of cells called neuro-mesodermal progenitors (NMP). These cells are capable of differentiating into mesoderm as well as (neuro-) ectoderm. NMPs are characterized by the fact that both transcription factors, Brachyury and Sox2 are active (expressed) in these cells at the same time. Previous studies have shown that Brachyury is necessary for the formation of mesodermal cells and of the trunk, while Sox2 plays a role in the development of neural cells and of the spinal cord. In addition, it is important for the maintenance of embryonic stem cells.

So far, it has been unclear how the descendants of Brachyury- and Sox2 double-positive NMPs decide to develop into the mesodermal or neural lineage. Therefore, scientists of the Department of Developmental Genetics at the Max Planck Institute for Molecular Genetics in Berlin carried out a broad investigation on the role and interaction of Brachyury and Sox2 in murine embryos. In the first step, the team led by Bernhard Herrmann generated embryonic stem cells with fluorescent reporter proteins, which indicate the gene activity of Brachyury and Sox2 in different colors. In this way, the researchers were able to isolate cell groups from the developing embryos, in which either Brachyury or Sox2 or both were active. Subsequently, the three cell groups were subjected to transcriptome analysis, meaning that all genes, that were active in the respective cell groups, were identified. This allowed the scientists to define gene groups that were differentially regulated in NMPs and their respective descendants, which had developed further into mesodermal or ectodermal germ layer cells. In addition, they managed to identify the genes controlled by Sox2 and/or Brachyury.

“Even though both transcription factors are active, target genes of Sox2 or Brachyury, that are important for the differentiation into neural or mesodermal cells, are not activated in NMPs”, Bernhard Herrmann explains. The target genes will only be activated in the descendants of the NMPs, which are ready for differentiation. “As the cells commence differentiation, a ‘fight’ for dominance takes place, in which both transcription factors activate their own target genes and, at the same time, suppress the target genes of the opposing lineage”, Herrmann goes on. In each cell, there is only one winner: When Sox2 takes over, the individual cell joins the neural lineage and when Brachyury wins, the cell becomes mesodermal. “It is still unclear, how the right proportion of mesodermal and neural cells is generated. Many more mesodermal than neural cells are formed”, Herrmann says. It is clear though that known signal molecules are involved. Mesodermal cells split into three subgroups, one of which forms the skeleton and skeletal muscles. Additional transcription factors control this process. The study also shows which transcription factors are responsible and which stages of differentiation they control.

The study presented describes in detail gene regulation networks controlling the formation of many tissues and organs. A better understanding of these regulatory mechanisms provides a basis for understanding how their dysfunction can lead to disease or malformations. Furthermore, they are important for the engineering of tissues of the trunk in vitro, e.g. cartilage or skeletal muscles, which one day might be used for therapeutic approaches.

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