Regeneration refers to the ability to replace tissue that has been lost with tissue that is functionally equivalent. Two fundamental questions need to be addressed with respect to the biology of regeneration: (1) how does regenerative growth differ from the growth that occurs during normal development? (2) Why can some tissues regenerate while others cannot? Drosophila imaginal discs, the larval primordial of adult structures such as the wing and the eye, are capable of regenerating after damage. Until recently, most studies of imaginal-disc regeneration involved culturing fragmented discs in the abdomens of adult female Drosophila. It was therefore difficult to conduct genetic screens for regulators of regenerative growth. Our laboratory has developed a way of studying regeneration in imaginal discs that does not require laborious surgical techniques. Expression of a pro-apoptotic gene for a short period in the developing wing pouch ablates most of the pouch tissue and leaves a rim of surviving cells. Regenerative growth restores the ablated pouch and adult flies can have wings of relatively normal size. An early event during regeneration is upregulation of the morphogen Wingless which results in increased levels of Myc protein;increasing Myc levels enhances regeneration. Additionally, regeneration occurs efficiently in discs from early third instar larvae but damage at the later third instar stage does not result in regeneration. Thus, as in many other organisms, a Wnt protein is upregulated during regeneration and the ability of imaginal discs to regenerate depends on the developmental stage. To understand how tissue damage initiates the process of regeneration, the properties of an enhancer of the wingless gene that is activated upon tissue damage will be characterized (Aim 1) and the signaling pathways that activate the enhancer will be defined. The mechanisms that prevent activation of the same enhancer in response to tissue damage in older larvae will also be characterized.
Aim 2 seeks to identify and characterize genetic alterations that promote regeneration in older imaginal discs.
Aim 3 will address the interrelationship between perturbations in imaginal disc growth and developmental timing.

Public Health Relevance

A number of common human diseases including heart attacks and strokes are characterized by loss of tissue that cannot grow back (regenerate). Some animals are capable of replacing damaged tissue very efficiently. To better understand the mechanisms that regulate the ability of a tissue to regenerate, we are conducting genetic studies in the fruit fly to identify and study genes that regulate regeneration;manipulating these genes could improve tissue regeneration.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1)
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Haynes, Susan R
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University of California Berkeley
Schools of Arts and Sciences
United States
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Hariharan, Iswar K; Serras, Florenci (2017) Imaginal disc regeneration takes flight. Curr Opin Cell Biol 48:10-16
Hariharan, Iswar K (2016) Size regulation blossoms in Kobe. Development 143:2691-5
Harris, Robin E; Setiawan, Linda; Saul, Josh et al. (2016) Localized epigenetic silencing of a damage-activated WNT enhancer limits regeneration in mature Drosophila imaginal discs. Elife 5:
Yoo, Sa Kan; Pascoe, Heath G; Pereira, Telmo et al. (2016) Plexins function in epithelial repair in both Drosophila and zebrafish. Nat Commun 7:12282
Hariharan, Iswar K (2015) Organ Size Control: Lessons from Drosophila. Dev Cell 34:255-65
Worley, Melanie I; Setiawan, Linda; Hariharan, Iswar K (2013) TIE-DYE: a combinatorial marking system to visualize and genetically manipulate clones during development in Drosophila melanogaster. Development 140:3275-84
Hariharan, Iswar K (2012) How growth abnormalities delay ""puberty"" in Drosophila. Sci Signal 5:pe27
Worley, Melanie I; Setiawan, Linda; Hariharan, Iswar K (2012) Regeneration and transdetermination in Drosophila imaginal discs. Annu Rev Genet 46:289-310
Gerhold, Abigail R; Richter, Daniel J; Yu, Albert S et al. (2011) Identification and characterization of genes required for compensatory growth in Drosophila. Genetics 189:1309-26
Siegrist, Sarah E; Haque, Najm S; Chen, Chun-Hong et al. (2010) Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila. Curr Biol 20:643-8

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