Date of Award

Spring 2026

Language

English

Embargo Period

4-27-2027

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biological Sciences

Program

Biology

First Advisor

ChangHwan Lee

Committee Members

Melinda Larsen, Alex Valm, Christopher Hammell

Keywords

stem cell, aging, niche, single-molecule, transcription, Notch

Subject Categories

Cell Biology | Developmental Biology | Genetics | Integrative Biology | Molecular Biology | Molecular Genetics

Abstract

Aging is a complex process that results in a progressive decline of tissue structure and function, which can lead to numerous diseases such as neurodegeneration and various cancers. During aging, stem cells decline in number and functionality, which has been linked to tissue aging and deterioration. The stem cell niche provides microenvironment to stem cells to regulate their cell fate and function and is thought to be responsible for stem cell aging indirectly. A precise understanding of the molecular mechanisms involved in stem cell and stem cell niche aging can provide insight into developing targeted treatments or the possible prevention of age-associated diseases. One of the major regulators of stem cell fate and the aging process is Notch, an intercellular signaling pathway that is involved in many biological processes such as cell fate decisions and tissue patterning. The dysregulation of Notch-transcriptional spatiotemporal pattern can disrupt processes such as cell proliferation and tissue polarity maintenance, linking Notch to many age-associated diseases. The model system, C. elegans, contains germline stem cells (GSCs) within its reproductive organ maintained through Notch signaling. In the C. elegans germline, Notch maintains a pool of GSCs by activating transcription of Notch target genes and of the known stem cell effectors sygl-1 and lst-1 in the distal tip cell (DTC), which serves as the stem cell niche. C. elegans is also a commonly used aging model due to similarities in muscle decline and fertility

My dissertation aims to examine GSC regulation during the rapid aging of the reproductive tissue of C. elegans. We examined the transcriptional spatial regulation of single-molecule RNA in situ hybridization (smFISH) to analyze the spatial regulation of both Notch target gene, sygl-1 and lst-1, and translational regulation of SYGL-1 and LST-1 during aging, where we show a disruption of spatial regulation due to the displacement of the signaling cell, DTC/niche, nucleus. MS2-MCP live RNA visualization system is utilized to precisely analyze the spatiotemporal changes in Notch transcriptional activation in the germline, where we find that Notch temporal regulation is intertwined with the spatial dysregulation. In addition, we investigate the aging and Notch regulation of the DTC/stem cell niche that maintains germline stem cells, to further uncover the mechanisms of stem cell and niche aging by analyzing Notch ligand expression, which is expressed only in the DTC/niche, during aging. We found an age-induced dislocation of the DTC/niche nuclear positioning that affects the GSC pool placement within the germline, turning to a Notch-independent mechanism of DTC/niche nuclear displacement. We examined the role and function of linker of nucleoskeleton and cytoskeleton (LINC) complex on DTC/niche nuclear positioning, by manipulating genes in the LINC complex and analyzing the effect on niche-GSC interaction and tissue polarity regulation. This work lends a deeper understanding of Notch spatiotemporal regulation during stem cell and niche aging that can contribute to therapeutics for Notch-related aging diseases.

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This work is licensed under the University at Albany Standard Author Agreement.

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Available for download on Tuesday, April 27, 2027

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