Department of Pathology
University of Zurich
Tel. +41 44 255 3945
Fax +41 44 255 4440
Elucidation of the roles of extracellular matrix chondroitin sulfate proteoglycans in the development of the peripheral and central nervous system (axon guidance, stabilization, regeneration, inhibitor, extracellular matrix, chondroitin sulfate proteoglycan, hyalectan, versican).
1 senior research fellow, 2 PhD students
In recent years significant progress has been made towards the understanding of molecular mechanisms that guide neuronal processes to their corresponding cellular targets. It has become increasingly clear that the pathfinding of the growing axons depends on a complex interplay between specific sets of receptor molecules on the advancing growth cone at the tip of the axon and positive as well as negative cues emanating from their environment. Different classes of molecules conveying either attractive or repulsive signals to the growth cones have been identified. Some of these molecules are diffusible factors providing long-range cues, others are cell surface or extracellular matrix components acting over short distance via cell-cell or cell-matrix contacts.
Among the extracellular matrix molecules, large hyaluronan-binding chondroitin sulfate proteoglycans (hyalectans) are thought to act as non-permissive short-range cues for axon advance through negative modulation of cell adhesion. Our previous studies analyzing the structure and expression pattern of the hyalectan versican revealed a close correlation between the spatio-temporal distribution of the alternative splice-variants V0/V1 and the formation of molecular boundaries, that flank or transiently block pathways of migratory neural crest cells and/or outgrowing axons during the development of the peripheral nervous system (fig 1). We furthermore identified a central nervous system specific isoform (versican V2), which is a major component of myelinated fiber tracts of brain and spinal cord. The expression of the versican V2 variant has been shown to coincide with the reduction of plasticity and regenerative capacity in the adult central nervous system. In accordance with these observations, we could recently demonstrate that intact versican isoforms isolated from various cell and tissue sources are indeed potent inhibitors of neural crest cell migration and axonal growth, in in vitro stripe-choice assays (fig 2).
Our ongoing projects currently focus on versican functions in vivo with the goal to gain new and detailed insights into its role in guidance, matrix stabilization and control of regeneration in the central and peripheral nervous system.
Figure 1: Versican V0/V1 distribution during limb innervation in the chicken.
Versican V0/V1 co-localizes with tissues that form transient barriers to motor and sensory axons. At E4 axons have reached the plexus region but are at that time point blocked from entering the limb bud by the pelvic girdle precursor. Only after versican-free pathways have formed at E4.5-5 the axons are able to proceed to their target tissues.
E: embryonic day; ax: axons; pg: pelvic girdle precursor, pl: plexus
Figure 2: Versicans inhibit neurite outgrowth and the migration of early neural crest stem cells
A) Neural crest cells migrate uniformly on fibronectin (FN) alone controls. In contrast, they avoid versican (VC; green) containing lanes and move exclusively along the fibronectin-only stripes. The migratory neural crest cells maintain their pluripotent character as revealed by the markers Sox10 (last panel: green) and p75NTR (last panel: red).
B) Similarly, neurites from retinal (RGCs) and dorsal root ganglions (DRGs) explants stained with an anti-neurofilament mAb (red) grow on the laminin-only substrate (LN) but avoid stripes containing laminin plus versicans (VC).
Wide range of protein chemical, immunological, cell and molecular biological techniques. FPLC, Phastsystem, automatic DNA sequencer.
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