Date of Award
5-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
Committee Chair/Advisor
David Feliciano
Committee Member
Lisa Bain
Committee Member
Julia George
Committee Member
Kara Powder
Committee Member
Emily Rosowski
Abstract
Billions of years of evolution have culminated in the most complex organ in all of biology: the brain. Its capacity to sense, store, and predict information uniquely bestows humans with the capability to generate art, music, language, and math and sets humans apart from other species. It is therefore prudent and worthwhile to study the brain and its development. A critical aspect of brain development is neurogenesis, or the production of neurons. Neurogenesis is facilitated by neural stem cells (NSCs) and is influenced by the mTORC1 signaling pathway. For NSCs to differentiate and become committed to a neuronal cell fate, mTORC1 signaling must decrease in amplitude. This is likely due to the role that mTORC1 signaling plays in regulating mRNA translation which are tightly controlled in NSCs.
Hyperactive mTORC1 signaling can result from the inactivation of either the Tsc1 or Tsc2 gene and is considered the main driver of symptoms in the developmental disorder Tuberous Sclerosis Complex (TSC). TSC is characterized by congenital growths that form in multiple organ systems, including the brain. In TSC, the brain has cellular abnormalities leading to three types of lesions: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). TSC lesions are associated with neuropsychiatric symptoms including epilepsy, autism spectrum disorders, intellectual delay, and behavioral abnormalities. Given the role that mTORC1 signaling plays in NSC differentiation, NSCs were examined in a Tsc2 null mouse model.
Briefly, genetic recombination was used to inactivate the Tsc2 gene in NSCs of the ventricular-subventricular zone. Tsc2 removal altered aspects of transcription and translation, including translational efficiency. Loss of Tsc2 caused striatal growths reminiscent of SEGAs. The growths contained NSCs and differentiated progeny including neurons and glia, possibly indicating abnormal neurogenesis due to Tsc2 loss in NSCs. There is evidence that Tsc2 loss, subsequent upregulation of mTORC1 signaling, and translational dysregulation cause NSCs to retain aspects of stemness, which could potentially contribute to TSC growth formation.
Recommended Citation
Riley, Victoria, "Loss of Tsc2 Results in Abnormal Postnatal Neurogenesis and Striatal Hamartomas" (2024). All Dissertations. 3582.
https://open.clemson.edu/all_dissertations/3582
Author ORCID Identifier
0000-0002-6542-7262