Date of Award
4-3-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Dihydroceramide desaturase converts dihydroceramides to ceramides in the final step of de novo ceramide biosynthesis. Reduction of dihydroceramide desaturase DEGS1 function in humans leads to hypomyelinating leukodystrophy-18, but the etiology of this disease remains unclear. Using mutants from a forward genetic screen, we discovered that infertile crescent (ifc), the sole Drosophila dihydroceramide desaturase, governs central nervous system development and morphology. ifc is primarily expressed in glia and acts cell-autonomously in glia to control glial morphology and function during nervous system development. Loss of ifc leads to severe glial defects, particularly in cortex glia, including endoplasmic reticulum expansion, glial swelling, compromised wrapping of neurons, and lipid droplet depletion. The glial phenotypes largely stem from disrupted lipid metabolism characterized by dihydroceramide accumulation, replacement of ceramide-derived sphingolipids by dihydroceramide counterparts, and increased phospholipid saturation via enrichment of 18:1-containing species. Our research supports a model in which retention of dihydroceramide in the endoplasmic reticulum of glial cells drives its expansion and disrupts glial function during nervous system development. Given the conserved nature of de novo ceramide biosynthesis, our findings in flies indicate that dihydroceramide-triggered expansion of the endoplasmic reticulum in glial cells, including the membrane-rich oligodendrocytes and Schwann cells, may be the proximal cause of hypomyelinating leukodystrophy-18.
Language
English (en)
Chair and Committee
James Skeath
Recommended Citation
Zhu, Yuqing, "Dihydroceramide Desaturase Governs Endoplasmic Reticulum and Lipid Droplet Homeostasis to Promote Glial Function in the Nervous System" (2024). Arts & Sciences Electronic Theses and Dissertations. 3082.
https://openscholarship.wustl.edu/art_sci_etds/3082