Publication Date
2016-07-15
Document Type
Doctoral Dissertation
Academic Program
MD/PhD
Department
Department of Neurobiology; Hong-Sheng Li Lab
First Thesis Advisor
Hong-Sheng Li
Keywords
Drosophila, intellectual disability, ACSL4
Subjects
Dissertations, UMMS; Coenzyme A Ligases; Developmental Disabilities; Drosophila; Intellectual Disability; Neuroglia; Neurons
Abstract
Recent developments in neurobiology make it clear that glia play fundamental and active roles, in the adult and in development. Many hereditary cognitive disorders have been linked to developmental defects, and in at least two cases, Rett Syndrome and Fragile X Mental Retardation, glia are important in pathogenesis. However, most studies of developmental disorders, in particular intellectual disability, focus on neuronal defects. An example is intellectual disability caused by mutations in ACSL4, a metabolic enzyme that conjugates long-chain fatty acids to Coenzyme A (CoA). Depleting ACSL4 in neurons is associated with defects in dendritic spines, a finding replicated in patient tissue, but the etiology of this disorder remains unclear. In a genetic screen to discover genes necessary for visual function, I identified the Drosophila homolog of ACSL4, Acsl, as a gene important for the magnitude of neuronal transmission, and found that it is required in glia. I determined that Acsl is required in a specific subtype of glia in the Drosophila optic lobe, and that depletion of Acsl from this population causes morphological defects. I demonstrated that Acsl is required in development, and that the phenotype can be rescued by human ACSL4. Finally, I discovered that ACSL4 is expressed in astrocytes in the mouse hippocampus. This study is highly significant for understanding glial biology and neurodevelopment. It provides information on the role of glia in development, substantiates a novel role for Acsl in glia, and advances our understanding of the potential role that glia play in the pathogenesis of intellectual disability.
Repository Citation
Quigley CM. (2016). The Drosophila Homolog of the Intellectual Disability Gene ACSL4 Acts in Glia to Regulate Morphology and Neuronal Activity: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M2XW27. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/839
DOI
10.13028/M2XW27
DOI Link
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Copyright is held by the author, with all rights reserved.
Included in
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Developmental Neuroscience Commons, Nervous System Diseases Commons