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Title: YAP-regulation of dynamic cell behaviour underlying organogenesis
Author: Porazinski, Sean
ISNI:       0000 0004 5357 1667
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2014
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In the vertebrate body each tissue/organ acquires three-dimensional (3D) structure during embryonic development and becomes aligned relative to other tissues/organs to generate the global body shape. The existence of a gene essential for orchestrating the complex process of building 3D body shape has not previously been suspected. Understanding the mechanisms by which 3D organs are built and organised is essential for the advancement of regenerative medicine, which aims to facilitate 3D tissue/organ formation and integrate these transplanted tissues/organs in the proper 3D alignment within the host to allow their full functionality. A large-scale ENU mutagenesis screen in medaka (Oryzias latipes) identified the hirame (hir) mutant where the morphogenesis of epithelial tissues is affected causing a flattened body in which individual organs/tissues collapse and are misaligned. The hir mutant also exhibits cell migration defects of the primary blood vessels and the heart. hir is a recessive lethal mutation with full penetrance and a robust phenotype. Positional cloning showed the unique hir phenotype is caused by a point mutation in the region of the Yes-associated protein (YAP) gene that encodes the WW1 protein domain of YAP. This mutant can therefore serve as a useful tool for the study of how 3D tissues and organs are generated and how they align to give rise to the global body shape. This work details how the combined use of medaka and zebrafish (Danio rerio) allowed the identification of YAP as essential for shaping the vertebrate body and its biophysical properties. In this thesis, it is reported for the first time that YAP is essential for the fundamental process of organogenesis at the whole-body scale. Analysis of YAP function in intact mutant animals by a variety of means including time-lapse confocal microscopy and intricate cell-transplantation experiments reveals a previously unrecognised but pivotal role for YAP. YAP governs various cell behaviours including oriented division and cell stacking to generate 3D tissues with proper tissue tension. In turn this tissue tension mediates extracellular matrix assembly and integrin signalling, which allows the correct alignment of adjacent tissues to produce functional organs that undergo coordinated morphogenesis to produce the overall 3D body shape. Furthermore, it is shown that these two major functions of YAP are mediated by actomyosin-dependent tension as demonstrated by in vivo force measurements.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available