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Posted: May 25, 2009
Insight gained into key molecule involved in development
(Nanowerk News) Scientists have shed new light on how cells interpret messages from the signalling molecule known as 'Hedgehog', which plays an important role in the development of organisms as diverse as flies, fish, mice and humans. Defects in the Hedgehog system have been linked to common birth defects and certain cancers. The findings, made by scientists in Austria and the US, are published in the journal Current Biology.
Many signalling molecules help to guide the development of an embryo, and Hedgehog is one of the most important, controlling the development of the extremities, the central nervous system, teeth, eyes, hair, lungs and the gastrointestinal tract. The concentration of Hedgehog varies throughout the developing body, and the concentration of the molecule determines whether the cells in a certain area will go on to form an arm or an eye, for example.
'The cells are told what to do not only because the molecule is present but also by the different concentrations of the molecules in the tissue,' explained Pia Aanstad of the Institute for Molecular Biology at the University of Innsbruck in Austria. 'The concentration of Hedgehog makes the thumb of the right hand grow on the left-hand side, and the thumb of the left hand grow on the right-hand side.'
Mutations in the Hedgehog signalling process can cause dramatic, often lethal deformities, such as the formation of one central eye instead of two eyes on either side of the face. A mutation in Hedgehog is also behind holoprosencephaly, which is one of the most common birth defects: the most extreme cases are characterised by severe brain defects and facial abnormalities. In addition, Hedgehog signalling problems have been linked to uncontrolled cell growth in certain cancers.
Norwegian researcher Dr Aanstad has been studying the Hedgehog signalling system in the tropical zebra fish for a number of years. A few years ago, she discovered a fish that had a mutation in a protein called Smoothened (Smo). The Smo protein is found on the cell membrane, where it is responsible for transferring the Hedgehog signal into the cell.
Further investigations revealed that the Smo protein is concentrated around the cilia, which are tiny hair-like projections that stick out from the cell.
In this latest study, the researchers highlight the crucial role played by a part of the Smo protein located on the outside of the cell; until now, this part of the protein was not thought to be necessary for the Smo function in vertebrates.
'By using high-resolution fluorescence microscopy, we have now shown that in the new mutants, a small genetic alteration at the extracellular part of this protein inhibits localisation in the cilia, and that while the cells identify the Hedgehog signals, they interpret the concentration incorrectly,' said Dr Aanstad. 'This is evidence for the notion that cells use various molecular mechanisms for interpreting different Hedgehog concentrations.'