Differentiation of the hypothalamus

Your body is made up of millions of different cells, which work together in a co-ordinated way. One group of cells that are really important in co-ordinating your body are nerve cells. A single nerve cells can integrate all sorts of information, decide what to do with it, and then instruct another cell to carry out a task in response.
It is difficult to exaggerate just how important are a set of nerve cells that are found in a small region of your brain, called the hypothalamus. Nerve cells here are responsible for maintaining your constancy: your temperature, weight, mood, to name but a few. They act by controlling other cells in a tiny gland just next to them ? the pituitary gland. Cells in the pituitary gland release hormones in response to messages sent to them from hypothalamic nerves.
Despite the huge importance of the hypothalamus, we know very little about how it forms in the embryo. Why do we want to know this? It is because the nerve cells that are found in the adult hypothalamus are actually born in the embryo. If we can understand how they develop normally, then we can hope to understand how they go wrong in disease and disorders. We may even be able to use stem cell technology to create new hypothalamic nerves.
Many of the questions that we wish to address in this proposal deal with the basic development of the hypothalamus: how do specific cell types arise within the hypothalamus?; how do early embryonic cell types underpin the later cells in the hypothalamus?; are the different regions of the later hypothalamus already set aside in the early embryo?

The proper functioning of the nervous system depends on the highly intricate patterning, regionalisation and specification of neural progenitor cells that occurs during embryogenesis. Recently we have shown that the ventral-most cells of the hypothalamus share an origin with floor plate cells. Like floor plate cells, ventral-most hypothalamic cells possess organiser activity, patterning and specifying cells in both the dorsally-adjacent neurogenic hypothalamus. The co-ordinated architecture of hypothalamic neurons is likely to be an instrumental component in the integrated development and function of the hypothalamo-pituitary-adrenal neuroendocrine axis, an axis that controls body homeostasis. These studies aim to examine the development and functional properties of ventral hypothalamic cells,and examine the specification and differentiation of cells in the neurogenic hypothalamus.

Many of the experiments within these categories follow the same general outline. In the first instance, we will analyse the chick embryo, perform in vivo and in vitro experiments/analyses, and test hypotheses through both gain-of-function and loss-of-function studies. Our background studies suggest that conditonal experiments will be critical to unravel hypothalamic development. The chick provides a particularly powerful model organism to study hypothalamic development, due to the ease with which it can be manipulated in both a spatial and temporal conditional manner. We will manipulate transcription factor codes in the hypothalamus through targeted electroporations. We will manipulate signals and signalling pathways in both in vivo and in vitro assays. We have extensive expertise in these areas. We will couple all these studies with fate-mapping analyses, since our previous studies have shown that cel migration events play a key role in hypothalamic ontogeny. However, in the longer-term, we will, where possible, use mouse mutants to assess whether hypotheses that derive through chick experiments are more broadly applicable.

My lab is well-equipped to perform these experiments and we have extensive experience in this area of research. There is a very real need to understand the ontogeny of the hypothalamus, since disorders of the hypothalamo-pituitary axis leading to aberrant homeostasis are likely to affect huge numbers of individuals.