Project Title: Control of the Sonic Hedgehog (SHH) signalling pathway by cell adhesion molecules in neural progenitor cells and medulloblastoma

Project Supervisors: Dr Andrew Furley (BMS and CMIAD) and Dr Freek van Eeden (BMS and CDBG)

Application deadline: Friday 14 December 2012.

Project description:

Background In order for tissues to grow in an orderly way, cell proliferation must be controlled. Although proliferation may be initiated by soluble ‘growth’ factors (EGF, FGF etc.), co-ordinated growth is likely to be controlled through direct contact between cells that ensures that cells divide and exit cell cycle at the correct time and place. We have identified a cell adhesion molecule (F3/contactin) expressed by mature cerebellar neurons that regulates the proliferation of their progenitors, suppressing responses to mitogenic signals from SHH. Dysfunction of the SHH pathway leads to the development of cerebellar medulloblastoma in mice and humans. Our recent data suggests that F3/contactin acts directly in the SHH signalling pathway.

Aims: This project aims to use the genetic tools available in zebrafish and mouse to dissect where in the pathway F3/contactin works. Our preliminary results suggest that transgenic misexpression of F3/contactin changes the outcomes of SHH signalling in fish. We would now like to extend this study to look at its affect on progenitor proliferation in the brain and compare this to the effect of blocking F3/contactin function using antisense morpholinos Subsequently, we will determine where in the SHH pathway F3/contactin acts by testing for epistasis to known SHH pathway mutants (e.g. Ptc, Smo). For instance, we will determine whether overexpression of F3/contactin can supress the hyper-proliferation found in Ptc mutants.

Contact details:

Dr Andrew Furley

Email: A.J.Furley@sheffield.ac.uk

Web: http://www.shef.ac.uk/bms/research/furley

Dr Freek van Eeden

Email: F.J.VanEeden@sheffield.ac.uk

Web: http://www.shef.ac.uk/bms/research/vaneeden