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Title: Exploring the roles of LIM domain binding proteins in zebrafish development
Author: Gu, Wenchao
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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As some of the most important and widely utilised intercellular signalling molecules, transforming growth factor βs (TGFβs) play critical roles in normal development and in human disease. Establishing appropriate levels of signalling involves positive and negative feedback, driven by the same signal transduction components, but whether or how the two are distinguished has not previously been understood. Here we show that LIM domain binding proteins (Ldbs) drive the Smad6/7-mediated negative feedback of TGFβ signalling, but they are not required for the ligand-driven positive feedback or other downstream transcriptional activation. In Ldb-deficient zebrafish embryos, the homeostasis of TGFβ signalling is perturbed. As a consequence, signalling of TGFβ family members, Nodal and BMP, is stably enhanced, giving rise to excess mesoderm and endoderm, an effect that can be rescued by reducing Nodal and BMP. Later in development, conditional ldb2a knockdown causes defective vascular, angiogenic and haemogenic development, likely also by elevating TGFβ signalling. Thus, Ldbs control the homeostatic regulation of TGFβ signalling and therefore play critical roles in diverse developmental processes.
Supervisor: Patient, Roger Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biology ; Zebrafish ; Development ; TGFb ; Ldb ; LIM domain ; Auto-regulatory feedback loops