Reversing to appreciate neuronal development

Many signalling pathways regulate the growth, development and branching of the nervous system. However, a group led by Prof Alun Davies, Cardiff School of Biosciences, has recently discovered a mechanism known as "reverse signalling" to be important in controlling the growth and branching of certain kinds of nerve fibres during development. 

The phenomenon of reverse signalling using members of the TNF signaling pathway has hitherto only been recognised to be important within the immune system. In their recent publication in the top journal Nature Neuroscience, the Cardiff team have demonstrated the importance of this signalling mechanism in regulating the growth of certain nerve fibres into tissues.

Classical signalling pathways involve the interaction of a ligand, or signalling molecule from one cell with a receptor on another cell, to invoke a response in the "receiving" cell.  This could be thought of as forward signalling.  If the ligand remains membrane bound, then cell-cell contact is required to stimulate the signalling response.  However, in the phenomenon of reverse signalling, the response is invoked in the ligand-bearing cell following the cell-cell contact.  Although TNF forward signalling has previously been recognized to be important in the nervous system in health and disease, this is the first demonstration that TNF ligand expressed on nerve fibres acts as a receptor for one of its conventional receptors present in the tissue into which the nerve fibres grow. Thereby, this reverse signalling promotes nerve fibre growth into tissues.

Professor Davies, who led the research, explained "It is interesting and important within the neuroscience field to understand how a hitherto unsuspected signalling mechanism plays such an important role in establishing the innervation of nerve fibres in multiple tissues. It is a tribute to the skill and hard work of the exceptionally talented scientists who made this important discovery and developed it to the point where it could be published in the leading neuroscience journal.  In particular, Lilian Kisiswa, the lead post-doctoral fellow, and two PhD students, Catarina Osorio and Clara Erice, made especially important contributions."

This funding was supported by a £1.3 million Welcome Trust program grant.