Dissertation
Characterization of Adnp functions from establishing neuronal morphology in neonates to functional circuitry in adulthood: implications for ADNP Syndrome and Autism Spectrum Disorder
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2022
DOI:
https://doi.org/10.17918/00001191
Abstract
Mutations in Activity-dependent neuroprotective protein (ADNP) are some of the most common genetic risks for developing autism spectrum disorder (ASD). Single-gene mutations in Adnp result in the complex neurodevelopmental disorder ADNP Syndrome which has hallmark symptoms including developmental delay, ASD, and intellectual disability (ID). Further developmental and neurological disorders such as tauopathy, Schizophrenia, Fetal Alcohol Syndrome, and Alzheimer's Disease have identified disrupted Adnp expression as a contributing pathogenic factor. Previous studies have identified Adnp as important for neural tube closure, autophagy, as a component of the BAF chromatin remodeling complex, dendritic spine formation, and as a cytoskeletal interaction partner. However, the etiology of ADNP syndrome is incompletely understood and therapies in mouse models have shown limited success. ADNP syndrome is a complex disorder with mutations that can be broadly separated into three categories: 1) mutations that lead to loss of Adnp function or haploinsufficiency; 2) mutations that result in mis-localization of Adnp, trapping it in either the neuronal cytoplasm or the nucleus; 3) mutations that result in overexpression of Adnp. Here, we defined Adnp's physiological functions from embryonic brain development throughout adulthood with a focus on neuronal shape and functional neural circuit formation. We also explored the consequences of both knockdown and overexpression of Adnp on cortical development. Specifically, we found that Adnp knockdown results in increased excitatory axon innervation throughout somatosensory cortices, increased dendrite formation, and subsequently increased connectivity and hyperexcitability between these brain regions. Conversely, we found that Adnp knockdown results in a failure of cortical axon targeting to thalamic nuclei resulting in decreased cortical input from the somatosensory cortex. We identified the downstream mechanism for how Adnp drives neuronal shape via Map6 binding and actin aggregation during early stages of neurite formation. Furthermore, we identified the mechanism responsible for Adnp nuclear/cytoplasmic localization which is important for understanding a subset of ADNP syndrome. We found that Adnp undergoes a localization shift at the onset of neurite formation, driven by PKC phosphorylation and subsequent 14-3-3 protein binding. This dissertation significantly builds upon our understanding of the physiological functions of Adnp during brain development as well as the etiology of ADNP Syndrome and ASD. Increasing knowledge of the development of ADNP syndrome from the molecular, cellular, and systems levels is crucial for both patient understanding and therapeutic innovation.
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Details
- Title
- Characterization of Adnp functions from establishing neuronal morphology in neonates to functional circuitry in adulthood
- Creators
- Sarah Anne Bennison
- Contributors
- Peter W. Baas (Advisor)Kazuhito Toyooka (Advisor) - Drexel University, Neurobiology and Anatomy
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 146 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine; Drexel University
- Other Identifier
- 991018388711804721