Anteriore Musterbildung im Wirbeltierembryo - Die Induktion von Vorderhirn und Herz

Abstract

Germ layers and body axes of a vertebrate embryo are established under the influence of a regulatory center, the embryonic organizer. Secreted factors emanating from the organizer and from its derivatives lay down the identity of neighbouring cells and coordinate embryogenesis. The first part of this thesis examined the role of the murine gastrula organizer as a source of anterior neural plate inducing signals. In mammals the initiation of forebrain induction is based on signals from the extraembryonic anterior visceral endoderm. Additionally, as shown in this study, signals from the tip of the primitive streak are necessary and sufficient for the establishment of a stable forebrain identity. The results led to a modification of the hypothesis on temporally and spatially separated head and trunk organizers in the mammalian embryo. Anterior neural induction can therefore be described as an extended activation-transformation model. Neural identity is initiated by extraembryonic endoderm and stabilized by the early gastrula organizer. Based on the observation that the prechordal plate, a derivative of the gastrula organizer, is a source for signals with an anterior establishing activity, an expression screen for novel factors involved in anterior patterning was performed. Genes cloned from a cDNA-library, made from prechordal plate tissue of headprocess stage chick embryos, were analysed in a large scale by whole mount in situ hybridization. The screen revealed a synexpression group, which members were expressed in endo-, meso- and mesendoderm, but not in the ectoderm of the prechordal region of gastrula embryos. Among those genes was the secreted Wnt-Antagonist cSzl. The characterization of this novel factor and its role in development was investigated in the second part of the thesis. cSzl was expressed in the anterior endoderm and the heartfield from stage HH4 to stage HH25 chick embryos and labels there the anterior pole of the hearttube. cSzl was regulated by the key signalling molecules of early pattern formation and cardiogenesis. The analysed regulative mechanisms allowed to postulate a model for the molecular network, leading to the establishment of the anterior lateral mesoderm in a vertebrate embryo with cSzl as a central component. During cardiogenesis cSzl was also a unique marker of the secondary heartfield, a key structure during the differentiation of the arterial cardiovascular system. Cells of the cardiac neural crest are in direct contact to cSzl expressing cells. Therefore Wnt-antagonism mediated through cSzl activity could be a novel mechanism involved in the septation of the truncus arteriosus and its misregulation could lead to congenital heart diseases like the human DiGeorge syndrome.