I. Functional characterization of novel connexin proteins in neuronal stem cells and mature neurons. 

II. Molecular basis of regeneration and degeneration in the nervous system: Role of gap junction proteins (Connexin) and integral membrane proteins of the tetraspan class (PMP22, Plasmolipin, Claudin).

III. Application of new technologies as tools to study differential gene expression (DNA-microarray, Proteomics, Lasermicrodissection, Real Time RT-PCR), protein-protein interaction (Y2H-Assay, SPR). For details please visit (link) my Functional Genomics Site

Function(s) of gap junctions in health and disease

The nervous system is immensely complicated and build by a huge number and variety of different cell types. One of the great questions is how appropriate responses to local changes in the environment of the developing and mature nervous system are coordinated and how the initiated processes may affect the function(s) of the adult nervous system and nerve repair during regeneration or degeneration. We are trying to address these questions, focussing on the role of cell:cell communication via electrical synapses (Figure 1). 

Electrical synapses (also named Gap junctions) comprise intercellular channels that allow the direct exchange of small metabolites (glucose, nucleotides, amino acids, etc.) as well as the transmission of ions for propagating electrical currents. They are formed by proteins, collectively termed connexins (Cx) that oligomerize in hexamers (connexons) that form hemichannels in plasma membranes. Hemichannels in adjacent membranes may form competent gap junctions under appropriate conditions. The activity of gap junctions can be regulated by the molecular composition, at the level of membrane voltage, pH, phosphorylation and biochemical signals. This leaves a rich potential for regulation of junctional conductance, directionality and molecular specificity. Arguably, the potential capability to synchronize, regulate or restrict the flow of information could be the most exciting role of gap junctional communication during neural development, in the adult nervous system and under pathological conditions. The connexin gene family is still expanding and more than 8 members have been found to be differentially expressed in the CNS and PNS with respect to cell specificity and developmental stage. Most interestingly, mutations in certain family members have been linked to the development of inherited neurodegenerative diseases. 

Historically, the role of electrical synapses was underestimated and all complex and higher brain functions attributed to the chemical synapses. This view has changed gradually during the last few years due to novel findings that demonstrate that electrical synapses can mediate synchronization of high frequency oscillations. This is a necessary prerequisite to synchronize neuronal activities needed for memory consolidation thus linking the activity of electrical synapses to higher brain functions. Work performed by our group and others has shown recently that different classes of neurons express specific subsets of connexin proteins. This implies that a gap junction mediated coupling of neuronal networks may exist which could have substantial roles under many physiological and pathological conditions. Neurons of the retina provide an excellent model to address this question, since the tissue is easily accessible and is composed of a specialized subset of neurons. Using genetic approaches and zebrafish as the animal model we are cloning and characterizing novel members of the connexin gene family. 

Neurons and glia cells in the central and peripheral nervous system have been described to express specific subsets of connexin proteins. Since these cells will respond in a specific and coordinated way to traumatic lesions and will participate in nerve repair we have set out to study the function of connexin proteins expressed in these cell types. We make use of molecular- and cell biological approaches to express wild-type connexin proteins or mutant forms of connexin protein in cultured neural cells or cell lines (Figure 2). These cell lines are used to uncover the function(s) of connexin proteins in vitro.

Very little is known about the impact of connexin activity on the Transcriptome and Proteom of a cell. We have established the technological platforms to investigate these questions using DNA-microarrays  and Proteom analyses (Figure 3).   

Taken together, the aim of our studies is to gain further insight into the complex composition of neuronal and interglial coupling and how a high degree of functional flexibility and responsiveness may influence development, the adult nervous system and impairment after traumatic lesions. The unravelling of the molecular mechanisms under normal and pathological conditions should lead to a better understanding of degenerative and repair events. 
 

For further reading:

1. Zoidl, G., Dermietzel, R. (2002)
   On the search for the electrical synapse: A glimpse at the future
   Cell and Tissue Research, in press
2. Evans WH, Martin PE. (2002)
   Gap junctions: structure and function.
   Mol Membr Biol:121-36.
3. Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Guldenagel M, Deutsch U, Sohl G. (2002)
   Structural and functional diversity of connexin genes in the mouse and human genome.
   Biol Chem 383:725-37
4. Dermietzel R. (1998)
   Diversification of gap junction proteins (connexins) in the central nervous system and the concept of functionalcompartments.
   Cell Biol Int 22:719-30.
5. Dermietzel R. (1998)
   Gap junction wiring: a 'new' principle in cell-to-cell communication in the nervous system?
   Brain Res Brain Res Rev 26:176-83