EASTBIO Role of HYPPO/YAP signalling in early development of the haematopoietic system
Second Supervisor: Dr Paul Reynolds, University of st Andrews
During embryonic development blood cells emerge from the endothelium of embryonic vasculature through the process called endothelial-to-haematopoietic transition (EHT). However, molecular mechanisms that underpin EHT remain poorly understood. Our preliminary data indicate that Hippo/YAP signalling is involved in blood specification during embryo development and in differentiation of embryonic stem (ES) cells. Hippo/YAP signalling is involved in various biological processes including regulation of organ sizes and tumorigenesis. This signalling is also involved in making cell fate choices, which can be triggered purely by mechanical forces, through the process called mechanotransduction. We hypothesise that mechanotransduction leads to Hippo/YAP-mediated switching of specific genes that are responsible for differentiation of blood cells from the embryonic endothelium.
In this interdisciplinary Project we will investigate the role of Hippo signalling and mechanotransduction in mammalian haematopoietic development using human ES cells as a model.
Our specific aims are:
1) Generation of fluorescent reporter cell lines to visualise haematopoietic differentiation and involvement of Hippo signalling in this process.
2) Analysis of Hippo/YAP signalling components in haematopoietic specification using overexpression and knockdown strategies in ES cells.
3) Analysis of the role of mechanotransduction in haematopoietic development using modulation of physical properties of substrates.
Methods. i. ES cell culture and differentiation; ii. confocal microscopy; iii. flow cytometry; iv. molecular biology (including CRISPR/Cas9, shRNA, ES cells transgenesis, QRT-PCR); v. single-cell transcriptome analysis; vi. interrogation of cell differentiation using physical forces; vii. Bioinformatics. Student will use a bioinformatics approach and collaborate with mathematicians and physicists – specialists in computer modelling to create a theoretical model for the role of mechanotransduction in haematopoietic development. The student will acquire expertise in haematopoietic development, gene manipulations, mechanotransduction and bioinformatics.
This is a collaborative project between 4 laboratories in the University of Edinburgh, University of Glasgow and the University of St. Andrews. Their expertise lie in haematopoietic development and differentiation (Prof. A. Medvinsky); cell signalling (Dr. P. Reynolds); role of physical forces in cell behaviour and differentiation (Dr. M. Vassalli); Bioinformatics (Dr. Al Ivens).
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Medvinsky, A., et al. (2011). "Embryonic origin of the adult hematopoietic system: advances and questions." Development 138(6): 1017-1031.
Dupont, S., et al. (2011). "Role of YAP/TAZ in mechanotransduction." Nature 474(7350): 179-183.
Dege, C. and C. M. Sturgeon (2017). "Directed Differentiation of Primitive and Definitive Hematopoietic Progenitors from Human Pluripotent Stem Cells." J Vis Exp(129).
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