Mysteries of the nerve cells


Gene Regulation, Stem Cells & Cancer Programme

The Epigenetic Events in Cancer group, led by Luciano Di Croce, is demonstrating the importance of the ZRF1 gene for establishing and maintaining the identity of the nerve progenitor cells.

Creating a human being from a single cell is an enigma that biologists have been trying to unravel for years. Before forming tissues and organs, the cells must be divided during the embryo's first hours. Some become neurones, whereas others make muscles, olfactory receptors or comprise parts of hard bone. But how does each of them know which of the body's cells to turn into? And there is more: when we are adult, our cells, which have the same DNA as those of the embryo, stay faithful to a tissue. So skin cells do not become liver cells, for example. Why is this?

The answer is found in a protein complex known as Polycomb, which is in charge of regulating gene action to establish and maintain cell identity. It is essential for correct embryonic development and is related to pathological processes like cancer, since it represses tumour suppressors. In 2010, researchers from the Epigenetic Events in Cancer group at the CRG, led by Luciano Di Croce, discovered how Polycomb proteins bond to DNA and are able to exercise their function in a cell. The work, published in the journal Nature, established the function of the ZRF1 gene in regulating embryonic development.

In order to coordinate and direct the destiny of each cell, some genes are responsible for activating or deactivating other genes that define their specialisation during development as well as, later, being involved in cell renewal for the maintenance of tissues and organs in an already-formed organism. ZRF1 is one of the genes responsible for each element doing what it is supposed to do. “When ZRF1 is active”, explains Di Croce, “it acts like a team of workers after a rockfall that opens the way to cell specialisation, pushing aside the proteins that block the transcription of the genes that will define its destiny”. If this mechanism fails, the cell becomes an uncontrolled cell.

The Epigenetic Events in Cancer group is still looking in depth at the ZRF1 gene. One of their most important recent contributions is a description of the molecular mechanisms underlying embryonic stem cell specialisation and the maintenance of the nerve progenitor cells (NPC), which was published in the journal Genes & Development, in 2014.

In particular, the researchers have discovered that ZRF1 is essential for establishing and maintaining the expression levels of Wnt ligands. Wnt signalling pathways regulate many functions in our bodies. Through cell surface receptors they pass signals to the inside of the cell (signal transduction), which causes changes in the transcription of the genes. The deregulation of Wnt signalling contributes to cancer and other degenerative disorders.

In order to reach this conclusion, the scientists removed ZRF1 from the nerve progenitor cells of mice and verified that the Wnt ligands did not activate correctly, causing neuronal development defects. “The initial study consisted of characterising the ZRF1 function in vitro, removing Polycomb in order to reactivate the genes. In this new study, we were able to demonstrate in vivo how that function was performed in a defined differentiation process like that in nerve cells”, explains Di Croce. “Regulating Wnt ligands is very important for the correct development of neurones”, concludes the CRG scientist.

In broad terms, the Epigenetic Events in Cancer group has focused, since its creation in 2003, on understanding the role of several protein complexes involved in the dynamics and metabolism of chromatin, the group of DNA, histone and other proteins located in eukaryotic cell nuclei, which when altered can lead to malignant growths.

Reference work

Aloia L, Di Stefano B, Sessa A, Morey L, Santanach A, Gutierrez A, Cozzuto L, Benitah SA, Graf T, Broccoli V, & Di Croce L. "Zrf1 is required to establish and maintain neural progenitor identity”. Genes & Development. 2014 Jan 15. 28(2):182-97.