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A microRNA program in the C. elegans hypodermis couples to intestinal mTORC2/PQM-1 signaling to modulate fat transport


"This intertissue dialogue between two specialized tissues is a remarkable strategy to precisely choreograph the transition to adulthood," says Robert Dowen, PhD, formerly of the MGH Department of Molecular Biology and lead author of the report. "It's quite surprising that C. elegans has evolved a very elegant mechanism to integrate developmental, metabolic and reproductive information for three distinct tissues at a very specific point in the growth of the animal."

Corresponding author Gary Ruvkun, PhD, MGH Department of Molecular Biology, says, "The microRNAs in the skin of C. elegans act like a clock. They control the developmental steps of the roundworm, culminating in a massive shift in fat metabolism towards production of eggs at the point of adulthood." Dowen was a research fellow in Ruvkun's laboratory prior to joining the Integrative Program for Biological and Genome Studies at the University of North Carolina at Chapel Hill.

Ruvkun's studies in C. elegans have led to many fundamental discoveries about the molecular control of development. In collaboration with Victor Ambros, PhD, now at the University of Massachusetts Medical School, Ruvkun discovered, via genetic analyses in C. elegans, the first microRNA and its mechanism of repressing the translation of messenger RNAs into protein. Ruvkun subsequently discovered that microRNAs are used in diverse organisms, including humans.

Once C. elegans larvae have hatched, they begin feeding on bacteria and grow rapidly, enlarging more than 100 times before reaching adulthood. Key steps in the transition from larva to adult are regulated by lin-4 and let-7, the first microRNAs discovered by Ruvkun and Ambros. When the roundworm reaches adulthood, nutrients that previously drove growth accumulate as fat in the intestine. But in order to reproduce, those fat stores need to be moved to reproductive cells in a process called vitellogenesis, which is accomplished through particles similar to the LDL molecules that carry lipids in humans and other mammals.

While insulin signaling is known to be essential to vitellogenesis, the research team suspected that additional pathways were likely to play a role in regulating the process. Their investigation revealed that regulation of vitellogenesis by means of expression in the hypodermis – tissue corresponding to the animals' skin – of lin-4, let-7 and the transcription factor lin-29 is mediated by the TORC2 signaling pathway in the intestine, which is involved with energy metabolism.

While several metabolic activities originally identified in C. elegans also apply to other animals, including humans, Dowen notes that whether mammalian lipid-transport molecules are controlled by the same proteins that regulate fat metabolism in C. elegans remains to be seen. "One of the questions we need to investigate next is what are the signaling molecules that couple hypodermal development to intestinal fat metabolism, including regulators of the TORC2 protein complex, which is a key mediator of cell growth and metabolism."

In addition to Ruvkun, who is a professor of genetics at Harvard Medical School, the co-authors of the Genes & Development paper are Peter Breen, Thomas Tullius and Annie Conery, PhD, of the MGH Department of Molecular Biology. Support for the study includes National Institutes of Health grant GM44619 and American Cancer Society postdoctoral fellowship 122240-PF-12-078-01-RMC.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service and returned to the number one spot on the 2015-16 U.S. News & World Report list of "America’s Best Hospitals."

Media contact: McKenzie Ridings, [email protected], (617) 726-0274

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