Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Anatomy and Cell Biology
Supervisor
Berube, Nathalie G
Abstract
Alpha-thalassemia intellectual disability X-linked (ATRX) is an ATP-dependent chromatin remodeling protein, and mutations in the ATRX gene are associated with ATR-X syndrome and autism spectrum disorder (ASD). Previous studies demonstrated that loss of ATRX in excitatory neurons in the postnatal forebrain leads to male-specific memory impairments without evidence of ASD features. It remained possible that an earlier inactivation of ATRX in neurons might yield a model to study ASD. To address this gap, we generated and characterized mice that lack ATRX expression starting at embryonic day 11, specifically in postmitotic excitatory neurons of the forebrain. Behavioural characterization of male and female conditional knockout (cKO) mice reveals ASD-like behaviors in adult mice of both sexes, although males display more extensive deficits than females. We observed significant morphological changes in the brain at one year of age, including increased cortical and decreased hippocampal volumes. Unexpectedly, alterations are seen in brain regions that retain ATRX expression, suggesting indirect effects of ATRX deletion in forebrain neurons on the development of other brain regions. Analysis of late embryonic cortical transcriptomes identified deficits related to translation and mitochondria in male and female Atrx cKO mice. By the second postnatal week, we found that the transcriptional profiles diverge between male and female Atrx cKO cortices. This included male-specific upregulation of genes related to the hedgehog pathway, cilia, and neuronal maturation, which coincided with a higher number of Ctip2+ neurons and increased synaptic density in deep cortical layers. We provide evidence that loss of ATRX in the male cortex triggers a precocious loss of epigenetic suppression of the neuronal maturation gene program, a change that is compensated for in the female cKO cortex. Overall, this study introduces a novel mouse model of ASD that exhibits sexual dimorphism in its presentation and highlights significant alterations in epigenetic and gene expression programming during a critical phase of brain development. Notably, the first two postnatal weeks are identified as a crucial period when female compensation mechanisms begin to emerge at the epigenetic and gene expression level.
Summary for Lay Audience
ATRX is a protein that helps regulate gene activity in the brain. When the ATRX gene is altered, it can disrupt brain development and lead to intellectual disability and autism spectrum disorder. Using mouse models, we aim to better understand how ATRX works and its role in brain development. Previous studies have shown that removing ATRX in brain cells after birth leads to memory problems in male, but not female, mice but does not cause autism-like behaviors. In this study, we wanted to see if removal of ATRX much earlier in the embryos might be a better model of autism. Our results show that when ATRX is deleted early, both male and female mice exhibit core autism-like behaviors, such as repetitive behaviors. However, males are more severely affected, showing increased sensitivity to sound, social memory difficulties, and social aggression. Imaging of the brains showed structural abnormalities that resemble those seen in individuals with autism. We also found that early changes in gene activity in both male and female mice disrupted critical cell processes and energy production necessary for brain development. After birth, we started to see major sex differences indicating that only the male brain cells begin to mature earlier than normal, which could change the brain connections that are made at that time. We demonstrate that these effects are likely caused by changes in chemical marks on the genes that activate them too early. Female brains do not show similar problems, suggesting that they can activate events to protect their cells from premature gene activation. In conclusion, we developed a new mouse model to study ASD and used it to show that the difference in severity of autistic features between sexes might stem from the ability of females to compensate for adverse events that occur in the first two postnatal weeks of life.
Recommended Citation
Quesnel, Katherine M., "Investigating developmental outcomes of ATRX ablation in embryonic excitatory neurons" (2025). Electronic Thesis and Dissertation Repository. 10674.
https://ir.lib.uwo.ca/etd/10674