No description available.

Thisbe (Ths) and Pyramus (Pyr) are the ligands for the Fibroblast-Growth-Factor (FGF)receptor Heartless (Htl), which is expressed in all mesodermal cells during gastrulation. To understand how these two FGFs orchestrate mesoderm spreading in gastrulation and mesoderm differentiation during organogenesis, loss and gain of function studies were performed. In an approach of functional analysis, a single mutant allele of ths was generated, ths759, for comparison of the single mutant conditions of ths and the null mesodermal cells to migrate and differentiate in a precise pattern.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 120-140).

Thesis (Ph. D.)--Cornell University, January, 2004. / Vita. Includes bibliographical references (leaves [170]-191).

Konstanz, Univ., Diss., 2004.

Thesis (Ph. D.)--Ohio State University, 2008.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22350号 / 医博第4591号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 斎藤 通紀, 教授 浅野 雅秀, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Roles for the Cdx transcription factors during anteroposterior patterning and development of the posterior embryo have been well described, yet little is known about Cdx functions during mesoderm specification. In the studies presented here, novel roles for Cdx during gastrulation are presented. In the first of two studies, the role of Cdx factors during cardiac mesoderm specification is investigated. We demonstrate that Cdx factors epigenetically restrict cardiac progenitor specification, preventing the ectopic expression of cardiogenic genes within progenitor mesodermal populations. We provide evidence to suggest that this occurs through interaction with Brg1, a subunit of the SWI/SNF chromatin remodeling complex, and propose a molecular mechanism by which Cdx-mediated recruitment of the SWI/SNF complex is required to maintain repression of cardiac targets at developmental stages where Cdx transcription factors are no longer expressed. Following this, Cdx-dependent gene expression programs were identified in the extra-embryonic yolk sac. RNA-sequencing of Cdx-mutant yolk sacs revealed novel Cdx-dependent gene targets involved in ion and nutrient transport, functions analogous to those previously described for Cdx in the adult intestinal epithelium. Subsequent experimentation revealed that, for a subset of these targets, regulation correlates with the maintenance of H3K27me3 marks. Finally, we provide evidence to suggest Cdx-dependent H3K27me3 marks are established at early developmental stages, when yolk sac progenitors are specified from the streak. Together, these studies describe novel roles for Cdx factors in mesoderm specification during gastrulation, and evoke molecular mechanisms by which Cdx might program early mesodermal populations for gene expression at later developmental stages through interactions with epigenetic regulatory complexes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20562号 / 医博第4247号 / 新制||医||1022(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 江藤 浩之, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

With so many deaths around the world being due to cardiovascular disease, there is great demand for an unlimited supply of cells for application in regenerative medicine. However, the control of directing pluripotent cells into mesoderm lineage which gives rise to cardiac muscle cells remains poor. Here in this work, the synergistic effect of chemical and mechanical signaling in driving cells towards mesoderm germ-layer was investigated. Transgenic reporter mouse embryonic stem cells were used in this study. The reporter cell line shows the cellular endogenous activity of pluripotency gene Oct3/4 with green fluorescent protein (GFP) while also reporting mesoderm-specific gene, Brachyury, activity with DsRed fluorescent protein. To promote adhesion of mouse embryonic stem cells and to initiate integrin-based mechanical signaling, the extracellular matrix protein fibronectin was used. In the presence of fibronectin and a small molecule called leukemia inhibitory factor (LIF), which is known to maintain pluripotency and self-renewal, mouse embryonic stem cells responded by exhibiting expressions of both GFP and DsRed. To further promote differentiation and to increase mechanical signaling, Notch signaling was activated by presenting cells with fibronectin and DLL1 protein. The differentiation was found to have a pronounced effect in the presence of fibronectin and DLL1 protein together with the withdrawal of LIF. This is a proof-of-concept that mechanical signaling together with synergistic chemical signaling can drive pluripotent cells towards mesoderm lineage. Future studies with human pluripotent stem cells may transduce cells towards mesoderm and finally towards cardiac fate. Collectively, this study shows the importance of chemical, but also the importance of mechanical signaling to transduce cells to mesoderm.