The functions of the transcription factor Pax6 in thalamic neuronal specification and axonogenesis

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In this research we are trying to discover why a single gene called Pax6 is so important for the normal growth of a critical part of the brain called the thalamus. The thalamus is essential for our ability to perceive the world around us since it transmits information about touch, temperature, pain, vision, hearing and so on through the brain to the cerebral cortex. The Pax6 gene codes for a protein that exerts high-level control of development by affecting the activity of other genes by binding to DNA. It is identical in mice and humans and when it is prevented from working the thalamus becomes seriously abnormal: it is too small, its cells contain some of the wrong molecules and it fails to make normal connections with the cerebral cortex. We still do not know if these are all of the defects and we do not know why they develop. Obtaining detailed answers particularly to the second of these questions will take a long time and here we plan to take a first step. We have designed experiments to compare all the major events that occur as the thalamus forms in normal mice and in Pax6 mutants of various types, to look for defects when Pax6 levels are lowered or raised. We shall examine thalamic cell production, the exchange of cells with adjacent tissue, molecules produced by thalamic cells and thalamic connections with the cerebral cortex. Where we show that Pax6 is needed for a particular process, we shall test whether the need is because Pax6 normally acts within the cells that show abnormalities. It is possible that some defects might be knock-on effects of changing Pax6 levels in other cells that then interact incorrectly with the cells showing abnormalities. To home in on the source of the defects we shall alter expression of Pax6 in specific sets of cells only, leaving others intact. Future work will build on results obtained here: we expect that by finding out which thalamic cells need Pax6 for which events we will be able to design further experiments to discover the biochemistry of Pax6?s actions within those cells.