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

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, understanding
morphogenesis 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 development
of 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.