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• W3090239342 abstract "The human cerebral cortex is comprised of billions of neurons and glial cells, all originating from apool of neural stem cells (NSCs) within the developing brain. NSCs retain their undifferentiated stemcell identity through self-renewal while also having the capacity to produce the three main cell typeswithin the nervous system, namely neurons, astrocytes and oligodendrocytes. The coordinatedproliferation and timely progression of NSC differentiation in both the developing and adult braindetermines the growth and functions of the cerebral cortex. A network of molecular mechanisms,including epigenetic regulators, transcription factors, and post-translational modifiers, temporally andspatially dictate the fate of NSCs. Disruption to these processes can result in malformations of corticaldevelopment (MCD), characterized by abnormal brain structure and size which in turn often manifestas intellectual disability, autism, epilepsy or other cognitive deficits. Mutations in numerous geneshave been implicated in MCDs and have since classified as clinical syndromes.This thesis addressed the underlying developmental mechanisms contributing to the abnormal corticalphenotype, namely macrocephaly and intellectual disability, in patients with mutations in threedifferent genes using transgenic mice as a model system. Firstly, heterozygous mutations in thetranscription factor called nuclear factor one X (NFIX) and histone modifier, nuclear receptor SETdomain containing protein 1 (NSD1), cause Malan syndrome (formerly known as Sotos syndrome 2)and Sotos syndrome (also Sotos syndrome 1) respectively. Both neurodevelopmental disorders arecharacterized by highly similar cortical abnormalities, including macrocephaly, intellectual disabilityand autistic-like traits. Although clinical assessments have determined the underlying symptomologyof both syndromes, the fundamental mechanisms contributing to the enlarged head circumference andintellectual disability in these patients remains undefined. In Chapter 2, I performed volumetric anddiffusion tensor magnetic resonance imaging (DTMRI) analyses on Nfix heterozygous mice to revealthat these animals have abnormally enlarged brain size and significantly abnormal corticalconnectivity between crucial areas of the brain, which may underlie the learning impairment andabnormal social behaviour in these animals. Collectively, these data provide a significant conceptualadvance in our understanding of Malan syndrome by suggesting that megalencephaly underlies theenlarged head size of these patients, and that disrupted cortical connectivity may contribute to theintellectual disability these patients exhibit. In Chapter 3, I examined the role of NSD1 during corticaldevelopment as very little is known about its function in the cerebral cortex. Firstly, I showed thatNsd1 was predominantly expressed neuronally in both the developing and adult brain. I furtheranalysed the morphological and behavioural characteristics of Nsd1 heterozygous mice, revealing behavioural characteristics reminiscent of some of the deficits seen in Sotos syndrome patients. InChapter 4, I further analysed the causes of intellectual disability in patients with mutations in thedeubiquitylating enzyme called ubiquitin specific protease 9 (USP9X). Using the rodent system, Ishowed that deficiency of USP9X activity during neurodevelopment results in the abnormaldevelopment of the hippocampus, aberrant neurogenesis in the adult hippocampus, and significantdeficits in cognitive function, which subsequently models and provides significant insight into theunderlying causes of intellectual disability in patients with USP9X mutations. Overall, this thesisprovides significant insight into how abnormal activity in various molecular mechanisms duringdevelopment of the cerebral cortex lead to highly similar cortical malformations, including abnormalbrain size and cognitive deficits." @default.
• W3090239342 created "2020-10-08" @default.
• W3090239342 creator A5046062510 @default.
• W3090239342 date "2020-09-04" @default.
• W3090239342 modified "2023-09-23" @default.
• W3090239342 title "Molecular mechanisms underlying malformations of cortical development" @default.
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