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But for the hair of a fly...
Researchers at Universite de Geneve (UNIGE) in Switzerland, are trying to understand this diverging mechanism and the stakes are extremely high. A stem cell that misses the correct way to divide asymmetrically can generate cancer cells that reproduce exponentially and form tumors, and not the asymmetric cell division that leads to healthy tissue diversity. The results of their original research were published 10 December 2015 in the journal Nature.
Now, in their current research published in Nature Communications, the scientists' further explore asymmetrical cell division, and how the two future cells "talk" to each other and divide their roles: as if saying "You'll become this, and I'll become that." They exchange information via proteins which carry that message. These proteins are themselves contained in tiny vesicles, called endosomes. Endosomes act as a kind of cellular memory card, and are responsible for instigating specialization by migrating to only one of the two daughter cells, where gene information will be processed and then transmitted to the sister cell. The key to the specialisation of one sister cell, lies in the ability of endosomes to move to the left or right of the mother cell. Upon cell division, the endosomes are only present in one of the two daughter cells. But how?
How do asymmetric divisions occur? How can a mother cell split into two daughter cells that are different from each other?
To analyse the phenomenon, a team led by Professor Marcos Gonzalez-Gaitan (from the biochemistry department at UNIGE) examined the hairs on the backs of fruit flies (Drosophila). These hairs are, in fact, sensory organs consisting of four cells capable of picking up the force and direction of the wind, which is critically important to a fly. Each hair — or sensory organ — originates from a single cell or SOP (sensory organ precursor), which first divides asymmetrically, producing two different cells, PIIA and PIIB. Each of these two cells also divides asymmetrically, generating a total of four final cells. An ideal setting for attempting to understand how — and why — endosomes move and make asymmetric division possible.
The first clue lies in the fact that the Sara protein is present in the endosomes, which propels them to group together on the same side of the mother cell. When genetically-modified, mutant flies are deprived of the Sara gene — and, by extension, the protein it produces. The SOPs divide symmetrically and the hairs do not form, the flies have naked backs without hairs. In the first phase of the research published in 2015, Professor Gonzalez-Gaitan's team was able to show that the same process occurs in other types of cells, such as intestinal stem cells and thanks to observations in fish, even in the vertebrate nervous system.
Sara provides the crucial piece of information, therefore, that decides which daughter cell will receive the endosomes. However, this does not explain why they assemble in only one of the two daughter cells. More detailed observation was required to understand this mechanism. Microtubules inside the mother cell serve as tracks for transporting endosomes, driven by a molecular motor called kinesin. The tracks are polarised (so they are one-way-roads) and the kinesin always moves in the same direction as the track dictates.
Some of the tracks lead to the left, others to the right of the mother cell, and the kinesin motor passes from one cell to the other, oscillating in the centre of the cell in a rapid sequence. Because there are more tracks pointing to one cell than the other, the endosomes with the key message are sent towards the correct cell. But in the end, endosomes need to escape from the track to be delivered to the PIIA cell, to make the hair cell. How?
To escape from this track and allow the endosomes to gather on the proper side, it is essential not only that the Sara protein is present, but also that it is bound to a molecular extension known as a phosphate group. Professor Gonzalez-Gaitan and his team succeeded in demonstrating the key role played by this phenomenon. Known as phosphorylation, it acts like a central switch signalling the start of the final migration of endosomes to the right cell. Without phosphorylation, the information could not circulate between cells, which would prevent any differentiation between the two daughter cells... condemning the flies to everlasting baldness! Anomalies in the way these fascinating molecular phenomena function in the cells lies behind the emergence of certain cancer tumors in humans.
Image credit: Study.com
The scientists observed that the positive or plus-end of the kinesin motor, Klp98A, pulls apart the centromere of a dividing cell to target Sara endosomes in the central spindle. As Klp98A can move in either direction on a microtubule, depending on which track it is on, Klp10A must use the protein antagonist called Patronin to decombine a microtubule and generate asymmetry in the central spindle.
This asymmetric spindle can now polarize endosomes to be sent into the other daughter cell. This mechanism demonstrates how cell division during anaphase inverts the polarity of the central spindle using Patronin nanobodies (single-domain antibodies). This inversion sends endosomes to the opposite forming cell, revealing the molecular and physical process by which organelles move away from the cellular cortex to be dispatched during an asymmetric division.
In flies, this process has been generalized to stem cells in the gut and the central nervous system; in zebrafish, the process generates neural precursor cells in the spinal cord.
During asymmetric division, fate assignation in daughter cells is mediated by the partition of determinants from the mother. In the fly sensory organ precursor cell, Notch signalling partitions into the pIIa daughter. Notch and its ligand Delta are endocytosed into Sara endosomes in the mother cell and they are first targeted to the central spindle, where they get distributed asymmetrically to finally be dispatched to pIIa. While the processes of endosomal targeting and asymmetry are starting to be understood, the machineries implicated in the final dispatch to pIIa are unknown. We show that Sara binds the PP1c phosphatase and its regulator Sds22. Sara phosphorylation on three specific sites functions as a switch for the dispatch: if not phosphorylated, endosomes are targeted to the spindle and upon phosphorylation of Sara, endosomes detach from the spindle during pIIa targeting.
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The hairs on the back of a fly are sensory organs consisting of
four cells produced by two asymetrical divisions.
Image Credit: UNIGE / Marcos Gonzalez-Gaitan.