Keeping Sonic Hedgehog Under the Thumb: Genetic Regulation of Limb Development

The development of a single fertilised egg into a complete organism with all its different cell-types is a complicated process. Each cell needs to know its relative position to the rest of the body, in order to know whether it should become bone, muscle, blood vessel, skin or any of the other cell types present. Traditionally the limb has been used as a model to study the mechanisms involved in patterning. For one, it is accessible for manipulations in the chicken egg, a feature that has been extensively used in classical embryology. Moreover, the limb is not essential for embryonic survival, allowing experiments that destroy the limb organisation to be followed over time. As a result, the development of the limb has been well characterised. Genetic analyses in the mouse have also added to our insights in limb development. The basic mechanisms during the development of the upper limb in chick and mouse (and human) are similar. The following chapter will describe the results from experiments performed either in mouse or chick and can be extrapolated to the human situation. Where differences are known to exist, they are indicated specifically. In this thesis, I will discuss the limb bud as if it were a pre-existing entity without connection to the rest of the body. This of course is a simplification of reality. Many of the signalling molecules and mechanisms discussed below are essential for patterning other parts of the body besides the limb buds. For example, Sonic Hedgehog is expressed in the developing notochord where it triggers a signalling cascade involving Wnt signalling, BMPs and FGFs, patterning the neural tube above.

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