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Understanding the Role of CLP1 in Messenger RNA Transcription and Neurodegeneration

LaForce, Geneva Rose
http://orcid.org/0000-0002-5046-5194
http://rave.ohiolink.edu/etdc/view?acc_num=case1657545334798463

Abstract Details

2022, Doctor of Philosophy, Case Western Reserve University, Genetics.
Balanced mRNA isoform diversity and abundance are spatially and temporally regulated throughout cellular differentiation. The proportion of expressed isoforms contribute to cell type specification and determine key properties of the differentiated cells. Neurons are unique cell types with intricate developmental programs, characteristic cellular morphologies, and electrophysiological potential. Neuron-specific gene expression programs establish these distinctive cellular characteristics and drive diversity among neuronal subtypes. Genes with neuron-specific alternative processing are enriched in key neuronal functions, including synaptic proteins, adhesion molecules, and scaffold proteins. Despite the similarity of neuronal gene expression programs, each neuronal subclass can be distinguished by unique alternative mRNA processing events. Alternative processing of developmentally-important transcripts alters coding and regulatory information, including interaction domains, transcript stability, subcellular localization, and targeting by RNA binding proteins. Here, we investigate the role of CLP1, a component of the 3’ end processing complex, and THOC6, a component of the transcription/export complex, in mRNA transcription. We find CLP1 suppresses proximal polyadenylation and disease-associated variants exhibit toxic gain-of-function properties. We establish a regulatory pattern for CLP1 in motor neuron 3’ end diversity and identify neuronal gene overexpression as a possible mechanism of disease. Furthermore, we find THOC6 is involved in regulation of splicing and is essential for neurodevelopment in the mammalian brain. Fine-tuning of mRNA processing is essential for neuronal activity and maintenance. Thus, the focus of neuronal RNA biology research is to dissect the transcriptomic mechanisms that underlie neuronal homeostasis, and consequently, pre-dispose neuronal subtypes to disease.
Ashleigh Schaffer (Advisor)
Peter Scacheri (Committee Chair)
Polyxeni Philippidou (Committee Member)
Helen Miranda (Committee Member)
Donny Licatalosi (Committee Member)
285 p.
Biochemistry; Genetics; Neurosciences
CLP1; THOC6; RNA processing; alternative polyadenylation; alternative splicing; mRNA transcription; neurodegeneration

Recommended Citations

Citations

  • LaForce, G. R. (2022). Understanding the Role of CLP1 in Messenger RNA Transcription and Neurodegeneration [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1657545334798463

    APA Style (7th edition)

  • LaForce, Geneva. Understanding the Role of CLP1 in Messenger RNA Transcription and Neurodegeneration. 2022. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1657545334798463.

    MLA Style (8th edition)

  • LaForce, Geneva. "Understanding the Role of CLP1 in Messenger RNA Transcription and Neurodegeneration." Doctoral dissertation, Case Western Reserve University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=case1657545334798463

    Chicago Manual of Style (17th edition)

case1657545334798463
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© 2022, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12