Of great importance during embryonic development are secreted signaling molecules that control the differentiation, proliferation and patterning of forming tissues. Many of these signals act in a graded fashion to control cell behaviour in a concentration dependent manner. Sonic Hedgehog (Shh) is an example of such a signal that controls the generation of distinct neuronal subtypes in the neural tube. In response to Shh signalling, the ventral neural tube is divided into compartmentalised progenitor pools, e ach of which generates distinct neuronal progeny.
The boundaries between adjacent progenitor pools are delimited by sharp, patent changes in gene expression and the remarkable precision of these boundaries, together with the absence of intermixing of cells from adjacent pools, represents a critical step in the interpretation of graded Shh signalling. Here we aim to determine the mechanisms involved in this poorly understood process. We will focus on the role of cell-cell contact and differential cell adhesion. To this end, we will develop novel in vitro and in vivo approaches that combine state-of-the-art live imaging techniques and the latest chick transgenic technology. These will allow me to assay this process and provide powerful functional tests for candidate molecules and analysis of the epistatic relationships between the different molecular partners.
The project addresses questions that are at the forefront of research in developmental neurobiology, and more generally in biology. Knowledge of the mechanisms that confer precision to graded Shh signalling will advance our understanding of neural tube development and provide insight into general strategies that endow morphogen gradients with their extraordinary accuracy. Moreover, the basic science quest ions addressed in this project are of direct relevance to basic and therapeutically applicable stem cell research, in particular, the use of stem cells for analysing and treating neurodegenerative diseases.
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