The nematode, Caenorhabditis elegans is an ideal animal model to study conserved
mechanisms of developmental and postdevelopmental processes. Here, I
describe the role of an Axin family member, pry-1, in aging, lipid metabolism,
and seam cell development. Our analysis of pry-1 animals showed a catastrophic
collapse of adult lifespan, which was accompanied with hallmarks of accelerated
aging. Transcriptome profiling of pry-1 mutants revealed altered expression of
genes associated with aging and lipid metabolism such as vitellogenins, fatty acid
desaturases, lipases, fatty acid transporters and genes involved in cuticle synthesis.
Consistent with this, pry-1 animals display significantly reduced levels of somatic
lipids. Knockdowns of vitellogenins in the pry-1 background restored lifespan and
lipid levels, suggesting that vitellogenins are necessary to mediate pry-1 function
in aging and lipid metabolic processes. Additionally, lowered expression of desaturases
and lipidomics analysis provided evidence of reduced fatty acid synthesis in
pry-1 animals. In agreement with this, an exogenous supply of oleic acid restored
depleted lipids in somatic tissues in addition to suppressing the short-lived phenotype
of worms. In addition, transcriptome profiling for differentially expressed
miRNAs in pry-1(mu38) identified heterochronic miRNAs (lin-4 and let-7 -family
members) to act downstream of pry-1 /Axin. In C. elegans, these miRNAs are
known to robustly regulate the stem-like, seam cell division. Loss of pry-1 function
caused heterochronic defects such that the seam cells divide precociously to
produce additional cells. The pry-1-miRNAs are involved in mediating silencing of
the heterochronic gene, hbl-1, a C. elegans hunchback homolog, to regulate seam
cell division. Furthermore, I report identification of novel miRNAs from C. elegans
and C. briggsae. Overall, our findings demonstrate a novel role of the Wnt signaling
regulator, pry-1/Axin, in the maintenance of adult lifespan that involves lipid
homeostasis and regulation of heterochronic miRNA to control the developmental
timing of seam cell division in C. elegans. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22095 |
| Date | January 2017 |
| Creators | RANAWADE, AYUSH |
| Contributors | GUPTA, BHAGWATI, Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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