Glypicans and FGFs in CNS Development and Function

Abstract

One of the most important events during central nervous system (CNS) development is the communication between cells. Cell-to-cell signaling implicates the interaction between a signaling molecules (or ligands) and their receptors. Ligand-receptor interaction is a tightly regulated process and is modulated at the cell surface by the action of glycoproteins such as Glypicans. Glypicans belong to the Heparan Sulphate Proteoglycans (HSPGs) and they consist of a core protein to which heparan sulphate glycosaminoglycan chains (GAG) are attached. Through these modifications Glypicans can bind different signaling molecules. The major topic of the research described in this thesis is the analysis of the function of one of the glypican gene, Glypican-4, during CNS development. I analyzed the spatial and temporal distribution of this gene during early mouse embryogenesis. Glypican-4 is expressed by the cells of different signaling center that are essential for correct anterior CNS development. Furthermore, I analyzed its function during the development of the forebrain using the Xenopus as animal model. I demonstrate that Glypican-4 is required for correct forebrain development and it does this by positive regulation of signaling molecules belonging to the fibroblast growth factor family (FGFs). In particular Glypican-4 and FGF are essential for correct dorso-ventral patterning of the embryonic forebrain. The forebrain is the most anterior CNS structure and in its dorsal aspect the cerebral cortex (the site of all the cognitive faculties) will arise in mammals. In light of the evolutionary conserved distribution of Glypican-4 both in mouse and Xenopus I suggest that Glypican-4 may regulate dorsal forebrain development also in mammals. In addition I have also analyzed the function of FGF-2 signaling in development and function of the autonomic nervous system. My studies indicate that FGF-2 signaling is essential for complete development of the neuronal circuitry required for central regulation of blood pressure.