Morphogenetic role of fgf8 and wnt8b in diencephalic development of vertebrate brainan experimental study in mouse and chick embryos

Resumen

During the embryogenesis, morphogenetic signals from neural organizers govern gene expression that specifies different cellular fates and regional characteristics of the brain. These inductive signals are molecules that belong to four genetic families: Wnt, Hh, Bmp and Fgf, defining positional identity in each compartment. Thus, the restricted expression pattern of these signals is crucial for the regulation of embryonic morphogenesis and cell fate specification. The diencephalon is a complex region in the brain which acts as a relay system receiving and filtering afferent sensory and motor information, relaying it on to other parts of the brain, is an interactive site between the central nervous system and the endocrine system, and is complementary to the limbic system. Over the last decade, the discovery of regulatory genes expressed in regionally restricted patterns in the developing diencephalon has provided predictions of the diverse morphological conceptions of the diencephalic organization. The aim of this thesis is to study the molecular and cellular mechanisms regulating diencephalic development. To this end, we have used experimental embryology technics, such as organotypic cultures, insertion of cells, beads and microbarriers, and inter- and intraspecific (isochronic, homotopic and heterotopic) grafts, to perform gain and loss of function experiments. Finally, embryos were processed by histological analysis, immunohistochemistry and in situ hybridization. In this study, we have evidences showing that reduced Fgf8 activity along the dorsal diencephalon results in complex alterations of cellular processes during epithalamic and thalamic development. These alterations include defects in cellular proliferation and migration, as well as in the expression of genes which regulate the patterning of the diencephalic alar plate. Moreover, we show evidences that Wnt8b generates a permissive territory for Shh expression in neuroepithelial cells in the diencephalic secondary organizer, by modifying the expression of other genes in the diencephalon. Finally, we correlate alterations in the expression of these genes with several human disorders.