Dissertation
Neuronal IL-17 controls C. elegans developmental diapause through CEP-1/p53
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2024
DOI: 10.25820/etd.007637
Abstract
During metazoan development, how cell division and metabolic programs are coordinated with nutrient availability remains unclear. Here, we show that nutrient availability signaled by the neuronal cytokine, ILC-17.1 switches C. elegans development between reproductive growth and dormancy by controlling the activity of the tumor suppressor p53 ortholog, CEP-1. Specifically, upon food availability, ILC-17.1 signaling by amphid neurons promotes glucose utilization and suppresses CEP-1/p53 to allow growth. In the absence of ILC-17.1, CEP-1/p53 is activated, upregulates cell-cycle inhibitors, decreases phosphofructokinase and cytochrome C expression, and causes larvae to arrest as stress-resistant, quiescent dauers. We propose a model whereby ILC-17.1 signaling links nutrient availability and energy metabolism to cell cycle progression through CEP-1/p53. These studies describe ancestral functions of IL-17s and the p53-family of proteins and are relevant to our understanding of neuroimmune mechanisms in cancer. They also reveal a DNA damage-independent function of CEP-1/p53 in invertebrate development and support the existence of a previously undescribed C. elegans dauer pathway.
Details
- Title: Subtitle
- Neuronal IL-17 controls C. elegans developmental diapause through CEP-1/p53
- Creators
- Abhishiktha Godthi
- Contributors
- Veena Prahlad (Advisor)Bryan T Phillips (Advisor)Steven H Green (Committee Member)Michael Dailey (Committee Member)Priya Issuree (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Integrated Biology
- Date degree season
- Summer 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007637
- Number of pages
- xvi, 225 pages
- Copyright
- Copyright 2024 Abhishiktha Godthi
- Language
- English
- Date submitted
- 06/19/2024
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 197-225).
- Public Abstract (ETD)
- This thesis explores an ancestral function for two conserved proteins, ILC-17.1 and CEP- 1/p53, in the free-living nematode C. elegans. ILC-17.1 shares similarities to immune response proteins called cytokines in mammals, and the IL-17 family of cytokines are amongst the most evolutionarily conserved. CEP-1 shares homology to the famous tumor suppressor, p53. In mammals, IL-17 cytokines are essential for mediating protection from bacteria and fungi, but when overactive, they trigger devastating autoimmune diseases like multiple sclerosis and psoriasis. p53 is a tumor suppressor and also one of the most commonly mutated gene in various cancers. I found that in C. elegans both ILC-17.1 and CEP-1/p53 play critical roles in development. ILC-17.1 release from larval neurons decides whether the larvae continue to grow into adults or arrest growth in a dormant state called dauer. ILC-17.1 permits growth by suppressing CEP-1/p53. Specifically, when food is abundant ILC-17.1 is released and suppresses CEP-1/p53 to allow development and growth to proceed. But when food is scarce, ILC-17.1 release is suppressed, CEP-1/p53 is activated, and the animal arrests in dauer instead. Interestingly, the mechanisms by which CEP-1 arrests C. elegans growth and development shares similarities with how mammalian p53 helps prevent cancer by controlling cell cycle progression and metabolism. Thus, my research uncovers a new pathway connecting cytokine signaling with metabolic regulation in C. elegans development, highlighting the conserved role of p53 in linking nutrient availability with developmental decisions. This mechanism may have broader implications for understanding nutrient-sensing and developmental regulation in other organisms, including humans, and could be useful in therapeutic approaches for diseases involving IL-17 and p53, such as cancer.
- Academic Unit
- Biology
- Record Identifier
- 9984698054402771
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