Mahmood, Mohammad Raasib;
(2024)
Developmental basis of the female excess in neural tube defects.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
RM_PhD thesis.pdf - Accepted Version Download (5MB) | Preview |
Abstract
Neural tube defects (NTDs) are severe congenital malformations affecting both cranial (anencephaly) and spinal (spina bifida) regions. Cranial NTDs are strongly female preponderant in humans and mice, whereas spinal NTDs show an equal sex ratio. This PhD project aimed to test the hypothesis that X-chromosome inactivation (XCI), the Xlinked gene dosage compensation mechanism, is responsible for female predisposition to cranial NTDs. XCI consumes methyl groups and is proposed to limit their availability in female but not male cells. This reduced methylation potential limits epigenetic modification of macromolecules such as DNA, histone and non-histone proteins which puts events such as neural tube closure at risk, making females susceptible to additional genetic or environmental challenges. Culture of wild-type mouse embryos during neurulation in the presence of the methylation cycle inhibitor, cycloleucine, produced cranial NTDs that were female preponderant. However, coculture with a further inhibitor, MGBG, which restored methylation potential, led to specific rescue of female cranial NTDs. Use of the DNA methylation inhibitor, Decitabine, induced cranial NTDs but these were not female preponderant, arguing against a major downstream role for DNA methylation. In contrast, protein methyltransferases, whose activities were predicted from measurements of methylation cycle intermediates, appeared more affected than DNA methyltransferases. Immunoblotting for SETD2-mediated trimethyl-lysine methylation, previously implicated in embryonic development, showed specific inhibition in female embryos with cranial NTDs. Combining low-dose Decitabine with cycloleucine treatment was found to rescue female embryos from cranial NTDs. This effect appeared likely to result from partial reactivation of an X-chromosome, as the rate of sex chromatin (Barr body) positive cells was reduced, and expression of X-linked genes was increased, specifically in rescued female embryos. This work supports the XCI-related hypothesis of female excess in cranial NTDs, and suggests a key role for protein methylation in the embryonic mechanism of cranial neural tube closure.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Developmental basis of the female excess in neural tube defects |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > 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 Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10198975 |
Archive Staff Only
 |
View Item |
