Title: Morphogenesis of the early mammalian embryo
Funder: Medical Research Council

Abstract: Organ systems are complex, three-dimensional structures built for highly specialized tasks, yet they arise from a relatively simple, uniform population of cells. Despite this initial simplicity, our knowledge of how early organ systems develop and the role that physical forces play in sculpting these complex tissue structures is extremely limited. Considerable effort has been devoted to understanding the role of gene expression in patterning tissues and organs, however very little is known about the mechanical properties required for their morphogenesis. We use the mouse embryo to investigate the fundamental problem of symmetry breaking in development — how a uniform layer of cells can be mechanically sculpted into a complex 3D structure that makes a functional organ. In particular, we are interested in the sequence of events and physical forces required for the initiation of one of the earliest organogenesis events, the formation of the foregut. The foregut arises from the definitive endoderm around embryonic day 8 and later develops into tissues including the oesophagus, lungs, liver, stomach, and the epithelial lining that surrounds the gastrointestinal tract. Despite being a critical structure necessary for the formation of major organ systems, the development of the foregut is poorly understood. Conventional microscopy systems have so far been unable to resolve or follow foregut development, as the events surrounding its formation occur both suddenly and rapidly, making their interrogation by fixed analysis extremely challenging. We have developed an advanced light-sheet microscope specifically tailored to the sensitive needs of the mouse embryo and are combining new technological improvements into -this microscope to not only interrogate but manipulate developmental processes live using techniques such as laser ablation or optogenetics. Our goalsare to use this imaging technology with the developing mouse embryo to not only determine the initial trigger(s) of foregut formation, but to also investigate where physical forces are originating from and how they are interpreted and translated by the embryo to differentiate one of the first organ systems from a uniform cell layer. This will require closely investigating the role of the cytoskeleton, physical forces, localized changes in gene expression, and coordination with neighbouring germ layers. This effort will reveal mechanisms that are likely re-used throughout the development of a wide range of tissues and organ systems. Defining the mechanisms of foregut development will lead to a detailed model of one of the earliest symmetry breaking events in the life of the mouse embryo, as well as insights into the coordination of the physical forces required for proper cell fate and tissue formation. The ability to one day repair damaged organs, treat developmental defects in utero, and even grow whole, functional organs outside of the body will depend on our understanding of how the embryo builds such complex structures.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL