Determining the role of boundary constraints and initial conditions on 4D cell morphodynamics during neural development.

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The aim of the project is to understand the biological and physical principles that underlie the acquisition and organisation of tissue shape.Developing organs typically start as simple tissues, which are often flat and contain only a few cell types. The tissue then "self-organises", meaning that it generates new shapes and cell fates without further external inputs. Understanding the generation of complex 3D shaped tissues from initially flat sheets remains a major challenge in biology. This process is driven by changes in the molecular and mechanical properties of the cells that shape the form and function of tissues. This process is iterative; e.g. as new contacts form between cells of different lineages, further rounds of organisation take place. Thus, understandingmorphogenesis lies at the interface between physics and biology as it involves cycles of changes in mechanics and gene expression that feedback across multiple spatiotemporal scales. Organoids have recently emerged as a powerful tool for investigating human organ development. Despite significant progress being made in a range of organoids, especially to replicate in vivo cell fate decision making, the biophysical processes that shape organs remain poorly characterised.In this project, Ryan will take advantage of neuruloids; this system replicates developmentof the early human nervous system. Ryan will culture neuruloids at Warwick. He will use state-of-the-art fluorescent imaging tools: spinning disc microscopy equipped with objectives for deep tissue imaging; and 2-photon microscopy. Further, Ryan will build an image analysis pipeline to extract 3D cell shape, cell tracking, and fate during neuruloid morphogenesis.Using this quantitative framework, we will address:1. how cells migrate during morphogenesis, and how cell fate feeds back into cellular motion;2. how constraints on culture size affect cell dynamics and the resulting organ shape;3. whether asymmetries in the underlying geometry (e.g. cells on either circular or triangular domains) alters organ morphogenesis, and if so, how?This project brings together the latest technologies in organoids and imaging to tackle a major question relevant to the MRC: how does complex organ shape emerge? Such information is highly pertinen to understanding diseases in adult which derive from defects during development.