Functional importance of HS carbohydrates in brain development.
APPLICATION DEADLINE 5th January 2015
Understanding the developmental mechanisms which create the CNS of healthy individuals is important for understanding neurological and psychiatric disorders with neurodevelopmental components. Although great strides have been made in identifying key regulators of this process our understanding is still rudimentary. Improving our knowledge base in this area is likely to impact on future attempts to understand disease and regenerate damaged circuitry.
While the roles played in signalling by proteins, secreted ligands and their receptors as well as transcription factors, has been intensively studied the roles played by carbohydates, while generally acknowledged as important, have been under-explored. Our research focuses on a class of membrane-associated and extracellular molecules called heparan sulphate proteoglycans (HSPGs) and more specifically on their carbohydrate component heparan sulphate (HS). HS interacts with signalling molecules critical for development so is well placed to coordinate developmental programs. The permutations of HS structural modification, largely as a result of differential sulphation, are so numerous that HS has the potential to be the most information-rich biopolymer known, making it an excellent candidate for regulating complex events involved in brain development and an important molecular system to understand.
The corpus callosum is a well studied model system for the development of complex neural structures and connectivity so is ideal for investigating the function of novel signalling molecules such as HS. We have identified HS modifying enzymes which are essential for normal callosal development proving the functional importance of differential HS sulphation in this sysyem (Conway et al., 2011; Clegg et al., 2014). We are now well placed to take this work to the next level and investigate the underlying cellular and molecular functions of the hitherto relatively unexplored HS molecule.
This project will explore how the controlled regulation of differential HS sulphation by HS modifying enzymes is an essential component of brain development. The project will use transgenic mouse, ex vivo culture, and/or imaging approaches to obtain a deeper understanding of the normal cellular and molecular functions of HS in the developing mammalian brain.
Clegg, J. M., Conway, C. D., Howe, K. M., Price, D. J., Mason, J. O., Turnbull, J. E., Basson, M. A.and Pratt, T. (2014) Heparan sulfotransferases Hs6st1 and Hs2st keep erk in check for mouse corpus callosum development, J Neurosci 34: 2389-401.
Conway CD, Howe KM, Nettleton NK, Price DJ, Mason JO, Pratt T. (2011) Heparan sulfate sugar modifications mediate the functions of slits and other factors needed for mouse forebrain commissure development. J Neurosci. 31:1955-70.
Pratt lab page
To apply for this PhD position please go to the Edinburgh Neuroscience PhD gateway page