The mechanism discovered in the brain of flies is associated with genes whose importance for the function of embryonic stem cells in mammals has long been known. This is the first time that a direct connection between the stem cell factors already known from mammals and the asymmetric division of stem cells in the brain of flies has been established.
Stem cells are vital because they are able to produce many different cell types from undifferentiated cells. This is of great importance both for the development of the embryo and for the regeneration of organs such as skin, intestine or liver. Stem cells can divide again and again, creating two daughter cells in each division. One cell that takes the path of differentiation and becomes a nerve cell, for example, and another cell that continues the cycle as a stem cell. This asymmetric division is crucial for their function. However, it has so far been unclear how this process is regulated.
Cell polarity of crucial importance
During asymmetric cell division, certain proteins are distributed in the cell in such a way that during division they only reach the daughter cell which will develop into a specialised cell. This state is called "polarized". A group of genes that control the polarity of the stem cell was already known. However, it has so far been completely unclear which factors switch on these polarity regulators in stem cells and are thus responsible for the maintenance of the stem cell. The doctoral student Katja Rust investigated this question in the fruit fly Drosophila by using the method of "reverse genetics" to switch off a large number of genes that had been identified in mammals as indispensable for the maintenance of stem cells.
Reunion with old acquaintances: Myc and the Tip60 complex
Finally Katja Rust found what she was looking for. She found a total of eight genes that led to significantly smaller brains when they were switched off in the stem cells of the nervous system. All eight genes have genetic information for subunits of the Tip60 complex. This complex is crucial in the regulation of transcription, the reading of genes, and is needed to maintain the ability of embryonic stem cells to divide in mammals. It was known that the Tip60 complex interacts with the transcription factor Myc. In fact, Rust was able to show that the loss of Myc also leads to smaller brains in the fly. Interestingly, many stem cells in these brains lose polarity due to the loss of a key regulator of polarity, atypical protein kinase C (aPKC). Rust was able to show that aPKC is switched on directly by Myc and the Tip60 complex.
"The function of the human Myc protein is the subject of intensive research, as it is one of the most frequently deregulated genes in human tumours," explains Andreas Wodarz. "When this gene gets out of control, the cells begin to divide uncontrollably. If the cells lose their polarity, the formation of metastases may be the result."
Significance in colorectal cancer
Myc and the Tip60 complex are now also being investigated by Wodarz and his doctoral student Hong Nguyen in another context: the stem cells of the intestine of the fruit fly. "Human colon in particular is one of the tissues where cancer often develops because stem cells get out of control. The fly is an interesting model because we can examine the stem cells very carefully and genetically modify them." The researcher particularly emphasises the transferability of findings from flies to humans: "It is more the rule than the exception. Almost every molecular signaling pathway known today is conserved and therefore works in a very similar manner in humans." Even though clinical application is still a long way off, basic research on model organisms is an indispensable step on the way to the development of new diagnostic and therapeutic methods.
Andreas Wodarz's research group is investigating the molecular mechanisms of cell polarity in different cell types. CECAD is an excellence cluster of the University of Cologne and the University Hospital of Cologne and researches diseases associated with aging.
Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila
Katja Rust, Manu D. Tiwari, Vivek Kumar Mishra, Ferdi Grawe and Andreas Wodarz
The EMBO JournalDOI: 10.15252/embj.201798659