Professor Philip Beesley

Personal profile

My research focuses on three related areas of molecular/cellular neurobiology:

The molecular mechanisms that underlie synapse formation and stabilisation

Synaptic junctions are highly specialised areas of contact and communication between neurones. They comprise the plasma membranes and underlying cytoskeleton of the pre- and post synaptic neurones. In particular the post synaptic nerve ending is characterised by the presence of a specialised region of the membrane cytoskeleton, the post synaptic density (PSD). One major suggested function of PSDs is to mediate recognition and adhesion events between the pre and post synaptic nerve endings via glycoproteins which project into the synaptic cleft. We have demonstrated that members of the cadherin family of calcium dependant adhesion molecules are major glycoprotein components of PSDs.

Current work focuses on the role of two synapse enriched members of the immunoglobulin superfamily identified and characterised in my laboratory. These glycoproteins have molecular weights of 65,000 (gp65) and 55,000 (gp55) and arise by alternative splicing of a single gene. Both of these transmembrane molecules contain two Ig domains. Gp65 contains an additional Ig domain at its N-terminus. It is expressed only by subsets of predominantly forebrain neurones and is most enriched in PSD preparations. In contrast gp55 is expressed in a range of tissues including brain and although it is a component of synaptic membranes, is not present in the PSD.

We are currently using a range of immunochemical and molecular biological techniques to establish the functions of these molecules. We are particularly interested to establish if gp65 plays a role in synapse formation and stabilisation. This work is carried out in collaboration with Professor E. Gundelfinger of the Institute for Neurobiology, Magdeburg, Germany.

The molecular and genetic basis of neuronal regeneration in model invertebrate systems. (Joint with Professor M. Thorndyke)

In contrast to the mammalian nervous system which shows only a very limited capacity for neuronal regeneration, several invertebrate nervous systems exhibit considerable properties of regeneration. These include the radial nerve cord of the echinoderm Asterius rubens and the neural ganglion of the solitary Tunicate Ciona intestinalis. Both of these systems are of major interest as models for studying the molecular events associated with neuronal regeneration and are relevant to understanding the limited regenerative capacity of mammals.

Our previous work has established the pattern of neurotransmitter expression in the regenerating neurones and investigated the sources of the precursor cells which give rise to the new neurones. In C. intestinalis our studies suggest that the new neurones are derived from at least two precursor populations: 1) the dorsal strand, a specialised epithelial structure, which runs posteriorly from the neural gland to the gonads, and 2) pluripotent hemocytes. The dorsal strand epithelium gives rise to small and medium sized neurones which are borne following ablation of the neural ganglion. The pluripotent hemocytes give rise to the large cortical neurones which are born prior to the ablation.

Our present major focus is to establish the spatial and temporal expression pattern of genes which control key events in formation of the new neurones in these regenerating systems. The genes of interest fall into two families of transcription factors: 1) The proneural genes which encode transcription factors containing a beta helix-loop-helix DNA-binding domain, and 2) genes which encode transcription factors containing a common DNA binding domain, the homeodomain. Proneural genes are important in determining neuronal lineage and homeobox genes in the control of the spatial patterning of cells. Our major aim is to establish the spatial and temporal pattern of expression of selected proneural and homeobox genes during neuronal regeneration, in both C. intestinalis and A. rubens. We are also carrying out studies to identify the chemical signals which induce the neuronal differentiation pathway in precursor cells.

The role of ubiquitin in neuronal stress responses and in neuronal development (Joint with Dr. C. Rider)

Ubiquitin is a low molecular weight polypeptide whose functions are mediated by its covalent attachment to a wide range of target proteins. One important function of such ubiquitination is to target proteins for rapid degradation by the 26S proteasome complex. However, ubiquitin has other functions as some ubiquitin conjugates, notably histone 2A, are rapidly and reversibly ubiquitinated.

Ubiquitin is of special importance in the nervous system. For example, Angelman syndrome, a severe form of congenital mental deficiency arises from a mutation which affects a specific ubiquitin conjugating enzyme, UBE3A. Studies in our lab. suggest that ubiquitin plays a role in dendrite outgrowth and re-modelling in the developing brain.

Currently our major interest is the involvement of ubiquitin in neuronal stress responses. One of the major classes of ubiquitin gene is induced by cellular stress such as heat shock. Studies carried out in our lab show that there is a marked elevation of ubiquitin conjugates and ubiquitin immunoreactivity following hypoxia-ischemia in immature rats and following ischemia in the adult rat. The rapid nature of this response suggests that it is a protective response, rather than merely a signal of cell death. Our major aim is to investigate the protective nature of this response by manipulating ubiquitin conjugate levels and the activity of its conjugation pathway in neurones and neurone-like cells both in vivo and in vitro. We are also studying the effects of ubiquitination of individual cytoskeletal and cell surface proteins.

In a separate project we are investigating ubiquitination in lymphocyte activation. By comparing the ubiquitin conjugates in resting and stimulated cells we hope to shed light on the role of ubiquitin in the activation mechanism.

Most recently as part of a major new initiative between RHUL, the Plymouth Marine Laboratory (PML) and Environmental Resource Technology (ERT), Edinburgh we are investigating the role of ubiquitin in environmental stress responses in marine invertebrates. This major multi-faceted project involves several senior scientists; at RHUL: Dr. P. Beesley; Dr. C. Rider; at PML: Dr. T. Hawkins; at ERT: Dr. Brian Roddie.

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