Chair of Biochemistry and Pathobiochemistry
Glial cells and neurons arise from the same pool of neuroectodermal stem cells. Whether a cell becomes a glial cell or a nerve cell is determined early in development. After the initial determination event cells continue to proliferate for some time, before they finally undergo terminal differentiation.
My group is interested in the identification and characterization of transcriptional regulators that participate in determination and differentiation of neural, in particular glial cells in the developing mammalian nervous system. We currently focus on POU domain proteins, and on Sox proteins. Analysis of these transcription factors will lead to a better understanding of developmental defects, tumor formation and regenerative processes in the nervous system.
Using transgenic mouse models, we have determined the function of the three closely related Sox proteins Sox8, Sox9 and Sox10 during nervous system development. We were able to show that Sox9, a Sox protein known to be affected in Campomelic Dysplasia and involved in skeletogenesis, is also present in stem cells of the peripheral and central nervous system. In the central nervous system, Sox9 expression starts shortly before neural stem cells stop to generate neurons and instead start to produce glial cells. Sox9 is essential for gliogenesis, so that in the absence of Sox9 determination of both main types of glial cells within the central nervous system is disturbed. Surplus neurons are formed instead of oligodendrocytes and astrocytes.
Sox10 expression starts during embryogenesis in the neural crest and many of its derivatives. Later, Sox10 expression becomes restricted to glial cells of the peripheral nervous system. At the same time, Sox10 also appears in the central nervous system where it is selectively found in oligodendrocyte precursors. Its expression lags behind that of Sox9. In the adult central nervous system, Sox10 is found in mature myelin-forming glia, the oligodendrocytes. Mutation or deletion of the Sox10 gene affects neural crest development. A Sox10-deficient mouse, which was generated in our lab, dies perinatally and completely lacks all glial cells throughout the entire peripheral nervous system. Similarly, melanocytes and enteric neural crest are missing. Oligodendrocyte development in the central nervous system is only affected at the level of terminal differentiation, and myelination does not take place. In the heterozygous state, mice are viable, but exhibit a combination of pigmentation abnormalities and aganglionosis of the distal colon. Sox10 target genes include several myelin genes, the gene for the receptor tyrosine kinase ErbB3 (in glial cells), and the genes for the transcription factor MITF and for the tyrosinase-related protein 2 (in melanocytes). Similar symptoms as in the heterozygote mouse model are observed in patients carrying Sox10 mutations and suffering from a combination of Hirschsprung disease and Waardenburg syndrome (HSCR/WS). Some of these patients additionally exhibit peripheral and central neuropathies.
Only minor symptoms such as an overall weight reduction were observed in mice deficient for Sox8, despite its close relationship to Sox9 and Sox10 and highly similar biochemical properties. Our studies show that in most tissues, Sox8 is co-expressed with Sox9 and Sox10 and exercises similar functions. Therefore, its loss is compensated by the remaining Sox9 or Sox10. Our current studies focus on the molecular mechanisms, by which these Sox proteins function, and their interplay.
The POU-domain protein Oct-6 (also known as Tst-1 and SCIP) is expressed both in glial cells and in neurons. Whereas glial Oct-6 has only been observed in nuclei, neuronal Oct-6 has also been detected in the cytoplasm. In agreement, Oct-6 is a nucleocytoplasmic shuttling protein with a nuclear localization signal and a nuclear export signal being both present in the DNA-binding POU domain.
Targeted deletion of the Oct-6 gene led to premature arrest of peripheral glial differentiation and a concomitant myelination defect in the peripheral nervous system. We detected Oct-6 also in glial cells of the central nervous system. Contrary to glial cells of the peripheral nervous system, however, oligodendrocytes of the central nervous system also express Brn-1 and Brn-2, two other closely related POU domain proteins. Redundancy between them might explain the absence of a severe myelination defect in the central nervous system following deletion of the Oct-6 gene. We have replaced the open reading frame of Oct-6 by the open reading frame of the related Brn-1 in the mouse. As a consequence, Brn-1 is expressed in this mouse at all places where Oct-6 is normally expressed. Despite this exchange of POU-domain proteins, Schwann cell development and peripheral myelination proceed completely normal. At least in peripheral glia, Oct-6 and Brn-1 are thus functionally equivalent.