Fast saltatory nerve conduction is a special feature of the vertebrate nervous system and depends on the production of myelin by specialized glial cells namely the oligodendrocytes in the central nervous system (CNS) and the Schwann cells in the peripheral nervous system (PNS). Myelin consists of protein-rich membranes wrapped around segments of an axon. Defects in oligodendrocytes or Schwann cells lead to absence or malfunctions of the myelin sheaths causing dys- or demyelinating disorders in humans including multiple sclerosis of the CNS or Charcot-Marie-Tooth disease of the PNS. During development of myelinating glia and the myelination process the cells pass through various stages that are controlled by an extensive network of transcription factors as well as by numerous and substantial epigenetic alterations. In recent years, progress has been made towards uncovering the underlying molecular mechanisms providing the basis for future therapeutic approaches for demyelinating diseases.
My research in this field focuses on the role of specific histone modifications, in particular the monoubiquitination of histone H2B at lysine 120 also called H2Bub1. This reversible histone mark is introduced mainly downstream of the transcriptional start sites of genes by the heterotetrameric Rnf40/Rnf20 E3 ligase complex. Rnf40/Rnf20 has been shown to interact with a number of transcription factors and is believed to act as a transcriptional coactivator. For our analysis we make use of cell culture systems as well as of loss-of-function mouse models. In the mouse models the gene for Rnf40 can be selectively removed by conditional gene deletion via Cre recombination from oligodendrocytes or Schwann cells and at different stages of their development. Since Rnf40 is absolutely necessary for the function of the ubiquitin ligase complex, deletion of the gene is sufficient to prevent the generation of H2Bub1. Using these mouse models, the H2Bub1 loss can be analyzed regarding its consequences on gene expression patterns, development of myelinating glia cells as well as on myelin production. The ultimate goal of these analyses is to unravel new potential targets accessible to pharmacological intervention in demyelinating diseases.

Transcription factors of the Sox family are important developmental regulators. They contain a high-mobility-group box as sequence-specific DNA-binding domain. The twenty mammalian Sox proteins can be subdivided into 10 groups according to sequence homology. We analyse the functions of the groupC proteins Sox4, Sox11 and Sox12 in nervous system development. The three proteins are highly homologous and show similar DNA binding properties and transactivation potential in vitro. All SoxC proteins are widely and dynamically expressed during mouse embryogenesis and are associated with many inductive and remodeling processes during vertebrate tissue and organ development. They are also involved in many diseases and regenerative processes, most prominently in tumor formation and progression. Expression patterns of the three proteins show extensive overlap complicating determination of developmental roles. The corresponding mouse mutants have revealed essential developmental functions for Sox4 and Sox11 with both deficiencies being lethal. Our analysis of Sox12-deficient mice, in contrast, revealed no overt phenotypic abnormalities.
Despite the well documented expression patterns, analyses of mouse mutants with single SoxC gene deficiencies have failed to reveal major defects in nervous system development leading to the hypothesis that their role may only become evident in mice with multiple SoxC gene deficiencies. Our goal is to unravel SoxC functions in the nervous system using conditional mouse mutagenesis, gene knock-down and overexpression strategies in the chicken embryo, as well as tissue culture and molecular biology methods.
We could show for the sympathetic nervous system that in the absence of both Sox4 and Sox11, sympathetic ganglia remain hypoplastic throughout embryogenesis because of consecutive proliferation and survival defects of sympathetic neurons. As a consequence, sympathetic ganglia are rudimentary in the adult and sympathetic innervation of target tissues is impaired leading to severe dysautonomia. Combined absence of both Sox proteins in the developing mouse spinal cord resulted in severe hypoplasia with extremely increased numbers of apototic cells throughout embryogenesis. These studies demonstrate that cell survival depends on Sox4 and Sox11 and that the two transcription factors have redundant functions as survival factors in neural cell types.