Delta-like homologue 1 (Dlk1) and Dlk2 encode vertebrate-specific transmembrane proteins belonging to the Jagged/Delta/Serrate family of Notch ligands. Murine Dlk1 is widely expressed during embryonic development and targeted deletion results in defects in numerous developmental processes, such as adipogenesis, haematopoiesis, neurogenesis and skeletal muscle formation. However, the mechanisms by which DLK1 regulates these processes remains unclear. The purpose of this project is to examine the function of these genes using zebrafish as an in vivo model, allowing insight to the ancestral functions of these genes. We have strong evolutionary evidence that dlk2 is the ancestral version of the gene from which dlk1 is derived; therefore, the thesis focuses primarily on the role of dlk2 in the zebrafish system. I initially examine the expression of zebrafish dlk1 and dlk2 during embryonic development and in the adult brain, determining similarities and differences between mouse and zebrafish. In particular, dlk1 and dlk2 in the fish exhibit a pattern that is more reminiscent of Dlk2 in the mouse. This developmental expression pattern is essential for the interpretation of the modulation of Dlk2 in later chapters, and is aided by the generation of a mammalian Dlk2 antibody that cross-reacts with zebrafish. We obtained a dlk2 mutant and used this line to examine the role of the DLK2 protein in development and in the adult brain. I demonstrate that, in the absence of DLK2, a population of neural precursor cells appear to over-proliferate early in zebrafish development. Later, by larval stages, these cells are absent, suggesting a premature activation and subsequent depletion of the progenitor cell pool in the mutant, reminiscent of the Dlk1 mutant in mouse. Associated with this phenotype are larval behavioral defects in motor response. In this thesis, it will be shown that in the adult dlk2 mutant zebrafish, the radial glial cell population in the telencephalon is completely depleted. These radial glial cells are thought to be responsible for adult neural regeneration in zebrafish, and our characterization of a mutant completely lacking this cell population provides a rich model to further examine and understand the functions of this well-studied but poorly understood cell population. These findings have both functional and evolutionary implications for the relative roles of these two vertebrate specific atypical Notch ligands.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第18905号 / 医科博第61号 / 新制||医科||4(附属図書館) / 31856 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 河本 宏, 教授 武田 俊一, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM