Chromatin remodelers are necessary players in modifying and protecting the chromatin landscape. Aberrant expression of these complexes can lead to epigenetic regulation defects, which is a common cause of neurodevelopmental disorders. Mutations in the BPTF gene, encoding the largest subunit of the NURF complex, cause the newly identified disorder called Neurodevelopmental Disorder with Dysmorphic Facies and distal Limb anomalies (NEDDFL). Recent research has identified a role for Bptf in progenitor proliferation and neocortical development. Here, we aimed to enhance the coverage of Bptf deletion in the neural system and we hypothesized that the phenotype of the Bptf knockout mice will recapitulate the human phenotype and will be a better model to study NEDDFL. We showed that Bptf conditional KO mice have major morphological brain defects, including an abnormal cortex and malformed hippocampus. Furthermore, assessment of these mice revealed key behavioural features found in NEDDFL patients.
The ATR-X syndrome, a severe neurodevelopmental disorder with autistic-like features, is caused by mutations in the ATRX gene that encodes an ATP-dependent chromatin remodeling protein. Previous studies have reported that, in the absence of Atrx, the glutamatergic and GABAergic networks are altered, which lead us to hypothesize that alteration of the equilibrium between the excitatory and inhibitory systems play a role in the pathogenesis of ATR-X syndrome. Here, we showed that mice with Atrx deletion in excitatory neurons (AtrxVgKO) and inhibitory neurons (AtrxVtKO) die embryonically or shortly after birth which precluded a thorough mechanistic analysis, yet they exhibited distinct hippocampal defects. Lastly, we generated a new conditional Atrx mouse mutant (AtrxEcKO) that survived beyond birth. Using this model, I showed that loss of Atrx caused a hypoplastic hippocampus, hyperactive and self-injurious behaviour that could be caused by altered myelinogenesis, axonogenesis, axonal pathfinding, cell differentiation and transcriptional regulation.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/45816 |
| Date | 09 January 2024 |
| Creators | Cardin, Valerie |
| Contributors | Picketts, David |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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