DOI

https://doi.org/10.25772/J98Y-M292

Defense Date

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

Azeddine Atfi

Second Advisor

Joseph Landry

Third Advisor

Rebecca Martin

Fourth Advisor

Paula Bos

Fifth Advisor

Larisa Litovchick

Abstract

TGIF1 belongs to the superfamily of homeodomain proteins, which regulate a wide variety of biological functions, including cell stemness and specification of cell fate during early development. Perhaps surprisingly, we found that enforced expression in pancreatic progenitor cells during embryogenesis resulted in severe diabetes, hinting at the possibility that TGIF1 might regulate pancreas development. Subsequent genetic experiments targeting β-cells showed that TGIF1 affected β-cell function and homeostasis. Transcriptomic analysis revealed that TGIF1 expression inhibits the expression of essential components of UPR signaling, underscoring a potential mechanism in which TGIF1 disrupts protein folding and secretion. Congruently, TGIF1 expression led to a dramatic disorganization of insulin within β-cells, accumulating as large aggregates, and was associated with decreased insulin secretion. Subsequent in vitro experiments showed that TGIF1 expression led to accumulation of insulin aggregates in the ER, thereby causing ER stress and concurrent impairment in insulin processing and secretion. In further support to these findings, conditional deletion of TGIF1 in pancreatic progenitor cells was also associated with hyperglycemia and diabetes, reinforcing the notion that TGIF1 physiological levels are instrumental to maintaining the balance between UPR and ER in β-cells. Finally, we serendipitously found that enforced expression of TGIF1 in β-cells recapitulated the cardinal hallmarks of neonatal diabetes, shedding important insights into mechanistic paradigms of this enigmatic condition.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

11-21-2023

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