Adrian J. Halme
- BA, Harvard University
- PhD, Massachusetts Institute of Technology
- Postdoc, Whitehead Institute
- Postdoc, University of California, Berkeley
- Assistant Professor, Cell Biology
Regeneration and Systemic Responses to Tissue Damage
Why do some animals have the ability to regenerate certain tissues and organs, while others have lost this capacity? The study of regenerative biology and medicine have shown that the ability of an individual tissue to regenerate is dictated by both cellular factors (extent of differentiation, capacity to initiate proliferation, and cellular ageing) and systemic factors (developmental progression, endocrine signals, metabolic state), but how these two levels of regulation interact to promote or restrict regenerative growth is an open question. The broad research focus of our laboratory is to investigate the mechanisms that control regenerative growth at both the cellular and systemic levels, and the interface between the two.
The regeneration of damaged imaginal discs--the larval precursors to adult tissues and organs--within the larvae of the fruit fly, Drosophila melanogaster, is an ideal experimental system for addressing these questions. Not only are there numerous genetic, molecular, and cell biological tools available in this classic developmental model system, but imaginal discs lose the ability to regenerate damaged tissue at a very specific time during larval development. Therefore, this system provides us with a tractable model for both understanding the local and systemic contributions to regenerative capacity, as well as how that capacity can be restricted.
We are identifying the molecular pathways acting within a damaged tissue that regulate regenerative growth by taking advantage of the available tools for clonal analysis in Drosophila imaginal discs. Using these tools, we have not only isolated genes that are specifically necessary for regenerative growth, but have uncovered an unexpected link to neoplasia and tumor development. Recently, we have isolated mutations that produce neoplastic tumors only in response to imaginal tissue damage. This result suggests that interactions between genetic (mutation) and environmental (damage and/or repair) factors within a tissue can contribute to loss of tissue integrity and tumor development in Drosophila tissues. The study of human tumor development and cancer has made it clear that localized tissue damage often plays an important, but complex, role in promoting tumorigenesis. We are therefore very excited to examine our mutants further to determine how this Drosophila system can inform our understanding of the complex interactions between tissue damage and mutation that lead to tumor development.
During our studies of imaginal disc regeneration, we have also focused on a systemic response to imaginal tissue damage that occurs just prior to the loss of regenerative competence: in the presence of damage within even a single imaginal disc, overall larval development will delay, extending the period of regenerative competence and allowing for further repair of the damaged tissue. We have shown that this delay results from the transcriptional regulation of a neuropeptide, PTTH, which is expressed in the larval brain and normally triggers the endocrine signals that both promote developmental progression and regenerative restriction. However, how damage in imaginal tissues is communicated to the promoter of the ptth gene is still unknown and an area of active research in our laboratory.
Our study of this phenomenon in fruit flies may also provide insights relevant to human disease. There are several clinical examples where localized, persistent tissue damage appears to alter global endocrine signals in patients. For example, prepubescent patients with chronic inflammatory diseases -- such as inflammatory bowel disease, cystic fibrosis or juvenile rheumatoid arthritis -- often experience a significant delay in the timing of puberty. In another example, there is evidence to suggest that the inflammatory signals produced within the adipose tissues of obese patients contribute to insulin resistance and type II diabetes. We suspect that our Drosophila model could provide a framework for furthering our understanding how local damage signals can produce effects on systemic endocrine pathways.
- Jaszczak J, Wolpe J, Dao A, Halme A. Nitric Oxide Synthase Regulates Growth Coordination During Drosophila melanogaster Imaginal Disc Regeneration. Genetics. 2015. PMID: 26081194
- Halme A, Cheng M, Hariharan I. Retinoids regulate a developmental checkpoint for tissue regeneration in Drosophila. Current biology : CB. 2010;20(5): 458-63. PMID: 20189388 | PMCID: PMC2847081
- Halme A, Bumgarner S, Styles C, Fink G. Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast. Cell. 2004;116(3): 405-15. PMID: 15016375
- Halme A, Michelitch M, Mitchell E, Chant J. Bud10p directs axial cell polarization in budding yeast and resembles a transmembrane receptor. Current biology : CB. 1996;6(5): 570-9. PMID: 8805277