Autism spectrum disorders (ASDs) are a heterogeneous class of neurodevelopmental disorders that share the three core behavioral symptoms of impaired social interactions, communication deficits, and restrictive and repetitive behaviors. Our previous studies identified the novel X-linked ASD gene NEXMIF (KIAA2022, KIDLIA). Mutations in NEXMIF leading to loss of its protein product are responsible for the development of autistic features and intellectual disability in humans. However, the role NEXMIF plays in brain development and ASD remains largely unknown. Therefore, I investigated the behavioral impairments and cellular and molecular dysregulation that result from loss of NEXMIF in a transgenic mouse model. I found that male NEXMIF-/y hemizygous knockout (KO) mice replicate the behavioral alterations reported in affected humans and that cultured neurons from NEXMIF-/y KO brains show a significant decrease in neurite outgrowth, synaptic protein expression, and spine and synapse density. Loss of NEXMIF in cultured neurons also leads to altered expression of many genes including several involved in synaptic development and function. Reintroduction of some of the downregulated genes in cultured neurons rescued the decreased spine density and synaptic AMPAR levels observed from loss of NEXMIF.
Several clinical reports have indicated that in females, haploinsufficiency of the X-linked NEXMIF gene causes symptoms similar to those observed in males lacking NEXMIF. Therefore, I examined the behavioral and molecular phenotypes in a transgenic mouse model of NEXMIF haploinsufficiency, female NEXMIF+/- mice. These animals displayed ASD-like behaviors, including impaired social interactions, repetitive self-grooming, and memory deficits. NEXMIF haploinsufficiency results in mosaic expression of the protein, resulting in two populations of neurons in the brain, those that express NEXMIF and those that do not. Interestingly, I found that both types of neurons demonstrated impairments in dendritic outgrowth, synaptic density, and the expression of important synaptic proteins. Together, these findings provide new insights into the cellular and molecular mechanisms of NEXMIF-dependent ASD and the role of NEXMIF in neurodevelopment, in both males and females.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/42973 |
| Date | 03 September 2021 |
| Creators | O'Connor, Margaret |
| Contributors | Man, Hengye |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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