Mechanisms of Foregut Formation in Mus Musculus

In mice, the foregut forms by the invagination of the anterior endoderm at embryonic day 7.5 and later gives rise to essential organs of the gastrointestinal and respiratory system. The formation of the foregut is critical for establishing the anterior organisation of the embryo, including the positioning of the heart and early brain. However, despite its fundamental role as one of the most significant shape-changing events in early post- implantation development, the mechanisms driving foregut formation remain poorly understood. This study presents the first in-depth morphological and molecular characterisation of the foregut formation in the mammalian embryo. By combining advanced long-term live imaging, chemical and genetic perturbation experiments, and RNA sequencing, I provide detailed insights into the cellular and molecular mechanisms that shape the foregut in mice. I show that the formation of the foregut in mice follows a stereotypic choreography of morphological changes, which are not driven by actomyosin contraction. Additionally, I demonstrate that the anterior endoderm of the forming foregut displays increased cell densities compared to the neighbouring endodermal regions. Within this region of increased cell density, I identify a spatially and temporally restricted apoptotic event affecting exclusively embryonic visceral endoderm (emVE) cells. These cells undergo programmed apoptotic cell death independently of P53 signalling and predominantly extrude incompletely toward the basal side. However, while this cell death event temporally coincides with the invagination of the anterior endoderm, it is not instructive for the invagination. Using tissue-specific Bcl2 overexpression in emVE cells, I show that in the absence of cell death, emVE cells form persistent, disorganised cell aggregates, indicating that removal of emVE cells is important for the formation of a normal foregut endoderm. RNA sequencing further reveals differential adhesion profiles between anterior emVE and definitive endoderm cells, providing insight into the potential mechanisms underlying selective emVE cell removal as well as aggregate formation in the absence of cell death. Taken together, this work contributes to our understanding of the mechanisms underlying the selective removal of visceral endoderm cells from the gut tube and provides a valuable framework for understanding the cellular and molecular mechanisms governing foregut formation and organisation of the anterior in early mammalian development.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Kretzschmar, Jenny

Advisor dc:contributor.advisor

• McDole, Kate

• foregut
• Mus Musculus
• developmental biology
• cell death
• Apoptosis

Licence

• https://www.repository.cam.ac.uk/bitstreams/887b6943-a9b8-4bda-ae7e-493bdce83a35/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.122761

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/391746