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The mouse as a model for exploring sex differences in Hirschsprung disease

Flower, Rosalyn; (2019) The mouse as a model for exploring sex differences in Hirschsprung disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Hirschsprung disease is a complex developmental disorder characterised by the lack of enteric neurons in variable portions of the distal gut. Importantly, Hirschsprung disease exhibits a strong sex bias with four times more males affected than females for reasons that are unknown. This thesis aims to understand how the sex bias of Hirschsprung disease arises by using the mouse as a model. Sex-specific differences in gene expression were characterised in the developing mouse enteric nervous system (ENS) to identify potential candidates for this sex bias. RNA-seq analyses were performed on mouse enteric neural crest cell derivatives (ENCCs) and mesenchymal cells at three timepoints of embryonic development: E11.5, E13.5 and E15.5. Differentially expressed genes in ENCCs were identified almost exclusively at E11.5 and E13.5, during which they migrate. E13.5 marked an important transitional phase with many genes specifically switch-on in female ENCCs and ENS-related pathways upregulated, suggesting advanced development of ENCCs in females compared to males. To identify a sex-biased mouse model of Hirschsprung disease, nine mouse lines with single or compound mutations of Ret, Sox10 and Ednrb genes, or modelling human Trisomy 21, were screened for a sex bias. While some sex differences were found in enteric phenotypes, these were not significant. Delayed migration of ENCCs found in the Trisomy 21 mouse model, however, provides the first in vivo evidence for the importance of chromosome 21 gene dosage in ENS development. Surprisingly, in a Ret51/51 mouse model, mutant females were underrepresented at P0, leading to a male:female sex bias of 3:1. Further investigation identified the lethality between E18.5 and P0, due to respiratory defects. These results propose an alternative hypothesis for the sex bias of Hirschsprung disease, whereby a male sex bias arises due to early lethality of females from causes outside the enteric nervous system previously missed.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The mouse as a model for exploring sex differences in Hirschsprung disease
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10069787
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