Date on Master's Thesis/Doctoral Dissertation

8-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Lovely, Charles

Committee Member

Cole, Gregory J.

Committee Member

Running, Mark

Committee Member

Samuelson, David

Committee Member

Watson, Corey

Author's Keywords

Ethanol; birth defects; development; genetics

Abstract

Craniofacial malformations lie at the heart of Fetal Alcohol Spectrum Disorders (FASD). While there is growing evidence for a genetic component to FASD, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. Bone Morphogenetic Protein (Bmp) signaling pathway dependent pouch formation is a key mechanism in facial development. We have previously shown that multiple Bmp mutants are sensitized to ethanol-induced facial defects. However, ethanol does not directly impact Bmp signaling. This suggests that downstream effectors, like nkx2.3 and Fibroblast Growth Factor (Fgf) signaling, may mediate the impact of ethanol on Bmp mutants. Here, I use an ethanol exposure paradigm with different Bmp and Fgf mutant lines and nkx2.3 knockdown approaches to test the mechanism of the Bmp-nkx2.3-Fgf pathway in pouch morphogenesis to understand the mechanism of ethanol induced facial defects in Bmp mutants. I combine morphometric approaches with immunofluorescence and Hybridization Chain Reaction to examine the cellular mechanisms underlying Bmp-ethanol interactions. I show that Bmp-ethanol interactions alter morphology of the endodermal pouches, independent of nkx2.3 gene expression and potentially through Fgf signaling. In addition, I did observe a significant increase in CNCC apoptosis in ethanol-treated Bmp mutants suggesting an ethanol sensitive, Bmp-dependent signaling pathway driving tissue interactions at the heart of FASD. Collectively, my work builds on the mechanistic understanding of ethanol sensitive genes and lays the groundwork for complex multi-tissue signaling events that have yet to be explored. Ultimately, my work provides a mechanistic paradigm of ethanol-induced facial defects and connects ethanol exposure with complex tissue signaling events that drive development.

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