Gene interactions in the specification of lens and olfactory progenitors

One of the most amazing inventions during evolution was the formation of complicated organs that can detect sound, smell and light / eyes, ears and noses. The development of these organs gave animals a major advantage over others because it allowed them to hunt for food, to avoid enemies, and even to communicate with each other / activities that are very difficult, if not impossible, without a sense of direction and cues like light, sound and smell to guide. In the most primitive forms of animals that possess such detection systems they are distributed over the entire surface of the body from head to tail. However, in more advanced animals / like in human beings / they are concentrated in the head and form relay stations transmitting information from our outside world to our brain. How do these organs develop in the embryo at the right time and at the right place? Why are they concentrated in the head? What makes them form always in the same arrangement? At the beginning of development, the embryo consists of three sheets of cells that will form different parts of the adult body. Cells that give rise to sense organs come from the same layer as the skin and the brain. How do they know whether to form a sense organ, the brain or the skin? And if a sense organ, how do they know which one to make? Most of these decisions are made very early in development and are regulated through molecules inside the cell that control which genes will be active and which ones remain silent. The molecules can be called 'regulators'. Cells that will make the smell-sensing cells in the nose contain a different set of regulators than those that will make the light-sensing structures in the eye. A 'regulator-code' determines the identity of a cell. In the last 10 years or so, it has been discovered that some of the regulators that control the formation of sense organs in the fly and in vertebrates are very similar or even identical. This has led to the fascinating hypothesis that although the structure of these organs and the way they function are quite different in different animals, the molecules that control their development may be very similar. To understand how cells that form the eye and nose become different from their neighbours and from each other, we will need to understand how the regulators work. The project we are planning investigates some of the regulators that are present in sense organs of flatworms, flies and vertebrates. How do these regulators work together to give a cell a particular identity? How are the regulators controlled? What are the molecules that switch them 'on' and 'off'? Understanding these basic principles will help us to understand how cells behave during normal development, how we can make stem cells differentiate into particular directions, how to repair aging cells and also how animals developed from blind and deaf creatures into forms with amazing abilities to sense signals from the environment.

The vertebrate lens and olfactory epithelium arise form similar structures in the head ectoderm, the cranial placodes. During early development precursors for both placodes are intermingled in the anterior, non-neural ectoderm, but subsequently segregate to localise to distinct primordia. We have found that before the onset of olfactory specific gene expression the entire anterior ectoderm containing placode precursors is specified as lens, suggesting that lens formation has to be repressed actively to allow cells to adopt olfactory fates. What are the molecular mechanisms that control this process? In this project we will investigate the transcription factor networks and signalling pathways that impart olfactory identity to non-committed ectodermal cells. We will use a combination of cell biology and biochemistry techniques together with molecular approaches in the living embryo to address this question. It is well established that the transcription factor Pax6 is required cell autonomously for lens formation; we have recently shown that the homeodomain protein Dlx5 antagonises Pax6 function during this process. Here, we will explore the molecular mechanisms of the Pax6-Dlx5 antagonism: we will investigate whether both proteins physically interact and how this interaction modulates their activity as transcription factors. These results will elucidate how transcription factors are controlled in a context dependent manner to confer cell identity. While Dlx5 prevents cells from adopting lens fate, it is not sufficient to impart olfactory character. We will therefore analyse the transcription factors that cooperate with Dlx5 to do so. Finally, we will identify the upstream signalling pathways that initiate the expression of olfactory specific genes and thus divert cells specified as lens towards olfactory fates.