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Origin and determination of the peripheral nervous system in the ascidian, Ciona intestinalis: role of the Notch signalling pathway and the cell cycle control mechanisms

Final Activity Report Summary - ASCINEURAL (Origin and determination of the peripheral nervous system (...): role of the Notch signalling pathway and the cell cycle control mechanisms)

Animals come in all sorts of sizes and shapes, yet they are all derived from a single cell, the zygote, which results from the combination of an egg and a sperm. Understanding how the amazing complexity of form and functions in adult animals is generated constitutes developmental biology's biggest challenge.

Biologists often prefer to work with small and simple animals to tackle these questions, under the assumptions that:
1. their development will be easier to understand than that of larger and more complex organisms;
2. the information obtained may help them to understand the basic rules that control the development of every animal.

I worked on a small invertebrate marine animal called 'Ciona intestinalis', or 'sea squirt'. Although the adult Ciona looks like a small sack, its larva looks pretty much like a tiny fish or a frog tadpole and thus makes a good model in order to study how the body shape of more complex animals is set up.

In particular, I was interested in understanding how the posterior peripheral nervous system of the sea squirt larva was formed. It was a very simple structure consisting of about twenty pairs of nerve cells found in the skin of the larval tail. These pairs of cells were scattered along the dorsal and ventral side of the tail and could be easily identified because each cell had a long, thin filament, called cilium. The larva probably used these cells to sense movements in the surrounding water and to adjust its own swimming behaviour.

Even though the peripheral nervous system of the Ciona larva had a very simple structure, there were at least two good reasons for studying it:
1. we could learn about the principles and mechanisms that controlled the formation of the nervous system in higher animals through its observation;
2. it was formed by a small, fixed number of cells, so it could assist us in understanding the mechanisms that controlled the proliferation of cells in other animals. This was a particularly interesting issue, because disruptions of these mechanisms were at the origin of major diseases such as cancer.

By means of a technique that allowed me to follow live individual cells during development, I found that the ciliated cells of the peripheral nervous system were born from the same parent cells that also gave rise to the surrounding, non-ciliated cells of the tail epidermis. I also showed that all dorsal and ventral cells of the tail epidermis had the potential to become nerve cells. However, at some time during development, this potential was lost by most of them and maintained only by a limited number, each of which would then split to form a pair of ciliated nerve cells.

Which were the responsible mechanisms for these phenomena? Together with other colleagues from the same laboratory I identified two soluble proteins, namely fibroblast growth factor nine (FGF9) and anti-dorsalising morphogenetic protein (ADMP), which were required to endow the cells in the dorsal and ventral epidermis of the tail with the potential to become nerve cells. Subsequently, I showed that a third protein, called NOTCH, acted as a receptor for a signal that restricted such a potential to only a limited number of cells. NOTCH also appeared to be involved in controlling the proliferation of the cells that were chosen to become ciliated nerve cells. Remarkably, it was known for some time that deregulations in the activity of NOTCH were responsible for some human cancers. This further supported our strategy to use the development of the larval peripheral nervous system of Ciona as a model to understand the mechanisms controlling the proliferation of cells in all animals. Therefore, after the project completion, I tried to identify the molecules directly involved in regulating the cellular proliferation and controlled by the activity of NOTCH.