Developmental Patterning and Cell Fate Specification in the Mouse Colon

Despite being only a single cell thick, the epithelium of the mammalian colon exhibits a remarkable degree of organisation. The epithelium is highly invaginated into glandular structures. These “crypts” provide the niche for the stem cells of the epithelium. Not only do such structures form during embryonic development, they can be regenerated after complete degradation as a result of injury. In recent years, a close connection has been made between these two processes, with the identification of foetal-like gene signatures in injured colonic epithelium. Despite this, the cell types and morphogenic mechanisms of the developing colon are still poorly understood. In this project, I set out to characterise the events and dynamics of the development of the colon. I began by describing the structural and transcriptional changes in development using a combination of confocal imaging and analysis of single-cell RNA sequencing data. In doing so, I identified not only a spatially heterogeneous developmental timeline along the length of the colon but also asynchronous maturation between the epithelial and mesenchymal compartments. By refining existing techniques to allow for ex-vivo timelapse imaging of the developing organ, I proposed and tested an epithelial-driven model for the formation of the stem cell niche before birth. Furthermore, by performing lineage tracing experiments, I was able to identify the mechanisms through which the postnatal expansion of the colon is tightly regulated. I also performed experiments to identify the mechanisms underlying the formation of large-scale epithelial and mesenchymal folding, which, although not conclusive, were able to rule out several proposed mechanisms. Altogether, I proposed a new model for the development of the colonic epithelium which is not only interesting for the developmental field, but also of significance to researchers wishing to understand how regenerative processes recapitulate developmental ones, challenging the idea of a single, developmental-like state.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Yin, Yanbo

Advisor dc:contributor.advisor

• Simons, Benjamin

• Colon
• Developmental Biology
• Intestine
• Patterning

Licence

• https://www.repository.cam.ac.uk/bitstreams/c8550c7f-e008-4d22-ba78-fe468f9e92b5/download
• http://purl.org/NET/rdflicense/allrightsreserved

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.118665

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/384767