This week we discussed four great papers from the Leopold, Halme, Gontijo (@alisson_gontijo) and Dominguez labs.
They all described how Lgr3 is the receptor for dILP8, a factor secreted from damaged organs to limit ecdysone release and slow organismal development and growth. While each paper made the same discovery, they did differ in experimental approaches and in some of their findings (which is not a bad thing).
All four were great papers – hopefully they receive the similar wide recognition that they each deserve.
Garelli A, Heredia F, Casimiro AP, Macedo A, Nunes C, Garcez M, Dias AR, Volonte YA, Uhlmann T, Caparros E, Koyama T, Gontijo AM. Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. Nat Commun. 2015 Oct 29;6:8732.
Colombani J, Andersen DS, Boulan L, Boone E, Romero N, Virolle V, Texada M, Léopold P. Drosophila Lgr3 Couples Organ Growth with Maturation and Ensures Developmental Stability. Curr Biol. 2015 Oct 19;25(20):2723-9.
We’ve fallen behind a bit (a lot!) on posting our regular lab journal clubs. So here are some of the papers we’ve discussed over the last year or so. What we liked about all these papers is that they each highlight the power and versatility of Drosophila genetics to answer important questions about physiology, metabolism and growth.
Sano H, Nakamura A, Texada MJ, Truman JW, Ishimoto H, Kamikouchi A, Nibu Y, Kume K, Ida T, Kojima M. The Nutrient-Responsive Hormone CCHamide-2 Controls Growth by Regulating Insulin-like Peptides in the Brain of Drosophila melanogaster. PLoS Genet. 2015 May 28;11(5):e1005209.
Koyama T, Rodrigues MA, Athanasiadis A, Shingleton AW, Mirth CK. Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesis. Elife. 2014 Nov 25;3. doi: 10.7554/eLife.03091
Rodenfels J, Lavrynenko O, Ayciriex S, Sampaio JL, Carvalho M, Shevchenko A, Eaton S. Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development. Genes Dev. 2014 Dec 1;28(23):2636-51.
Brankatschk M, Dunst S, Nemetschke L, Eaton S. Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling. Elife. 2014 Oct 2;3.
Tiebe M, Lutz M, De La Garza A, Buechling T, Boutros M, Teleman AA. REPTOR and REPTOR-BP Regulate Organismal Metabolism and Transcription Downstream of TORC1. Dev Cell. 2015 May 4;33(3):272-84.
Kim J, Neufeld TP. Dietary sugar promotes systemic TOR activation in Drosophila through AKH-dependent selective secretion of Dilp3. Nat Commun. 2015 Apr 17;6:6846.
Chatterjee D, Katewa SD, Qi Y, Jackson SA, Kapahi P, Jasper H. Control of metabolic adaptation to fasting by dILP6-induced insulin signaling in Drosophila oenocytes. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17959-64
Hasygar K, Hietakangas V. p53- and ERK7-dependent ribosome surveillance response regulates Drosophila insulin-like peptide secretion. PLoS Genet. 2014 Nov 13;10(11):e1004764.
Sun X, Wheeler CT, Yolitz J, Laslo M, Alberico T, Sun Y, Song Q, Zou S. A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila. Cell Rep. 2014 Sep 25;8(6):1781-92.
Ulgherait M, Rana A, Rera M, Graniel J, Walker DW. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014 Sep 25;8(6):1767-80.
Park S, Alfa RW, Topper SM, Kim GE, Kockel L, Kim SK. A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion. PLoS Genet. 2014 Aug 7;10(8):e1004555.
In a recent lab journal club we discussed a paper from the lab of Aurelio Teleman:
DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth.Nature 2014 Aug 14; 512(7513):208-12
This very nice paper describes the role for density-regulated protein (DENR)-multiple copies in T-cell lymphoma-1 (MCT-1) in the control of mRNA translation and growth in Drosophila. In particular, the authors show that DENR-MCT-1 is required for translation re-initiation of mRNAs containing upstream open reading frames (ORFs). Interestingly, these mRNAs include both the insulin receptor (InR) and ecdysone receptor (EcR), both of which are necessary for normal larval growth and development.
A great deal of work has focused on transcriptional control of growth in Drosophila. This study provides an excellent example of how selective control of mRNA translation plays an important, yet often unappreciated, role in tissue growth.
In a recent lab journal club we discussed a recent paper from the Pilpel and Lund labs:
A dual program for translation regulation in cellular proliferation and differentiation.Cell 2014 Sep 11; 158(6):1281-92
Transfer RNAs (tRNAs) are essential for mRNA translation. However, tRNA synthesis is often considered merely a ‘house-keeping’ function. Moreover, a role for tRNA synthesis as a regulatory step for protein synthesis is largely ignored because it is assumed tRNA levels are maintained in excess. However, recent studies suggest otherwise: our lab showed that in Drosophila, elevated tRNA synthesis – and increased tRNAiMet in particular – can increase mRNA translation, drive tissue and body growth, and accelerate development (Rideout et al, 2012, PNAS). In addition, the lab of Tao Pan ( RNA 2013 Apr; 19(4):461-6) showed that increased tRNAiMet can promote proliferation in cultured mammalian epithelial cells.
In this wonderful paper from the Pilpel and Lund labs, the authors describe even more intricate links between tRNA and translation. They use tRNA microarray analysis of multiple cell types to, first, show that the relative levels of tRNAs within the total pool change depending on proliferative vs. differentiated status of cells, and, second, that these differences in tRNA expression patterns match predicted mRNA codon usage in the types of gene expressed in proliferating vs. differentiating cells. The paper contains many other striking observations, including those that may explain these selective tRNA expression changes and those that point to the widespread nature of the correlation between tRNA and codon usage. But, together, these data suggest the intriguing hypothesis that cells alter their tRNA expression patterns to match changes in codon usage in their mRNA transcriptomes.
Books that educate, stimulate and inspire (part 2).
Scientific research is portrayed as an objective pursuit, but it is always influenced by an array of subjective emotions – joy, frustration, rejection, validation, egotism, confidence, worry, friendship, competition, intuition, luck, success, failure. For better or worse, it is these forces that often determine how discoveries are made and how science is communicated.
I enjoy reading books that delve into the stories behind research discoveries and that reveal the passion, politics and personalities that drive scientific research. About a year ago, I compiled a list of books that I recommend (click here to see them). Here is a new list of more recent books I’ve read. I hope you enjoy these. Feel free to suggest others – I’m always looking for a good read.
Blue skies and bench space: Adventures in Cancer Research by Kathy Weston. A fantastic and enjoyable description of the science, scientists and personalities at the Imperial Cancer Research Fund Laboratories in London, especially during the ‘70s and ‘80s, when the ICRF was at the forefront of research in developmental biology, cell cycle control, apoptosis and cancer. The book also serves as an excellent companion and comparison to “Life Illuminated” (below). You can also read the book free online here.
Life Illuminated: Selected Papers from Cold Spring Harbor
Volume 2, 1972–1994. An account of some of the key papers that emerged from CSHL at a time when the Laboratory was producing some of the key breakthroughs in our understanding of DNA replication, transcription, tumor viruses and cancer biology. Each paper has a commentary from one of the investigators involved in the work.
Paths to Innovation: Discovering Recombinant DNA, Oncogenes, and Prions, in One Medical School, Over One Decade. and Ambition and delight. by Henry Bourne. These are two enjoyable books from Henry Bourne. The first (Paths to Innovation) is a wonderful account of an exciting period in the history of UCSF, when the University recruited and fostered young, talented scientists who went on to make Nobel prize-winning fundamental discoveries in molecular and cellular biology. In the second book (Ambition and Delight) Henry Bourne provides an honest, enjoyable and often funny account of his career in academic research – an excellent book for young scientists embarking on a career in research.
Apprentice to genius. The Making of a Scientific Dynasty. By Robert Kanigel. A wonderful book that describes a dynasty of mentor-protégé relationships among a group of brilliant neuroscientists (Steve Brodie, Julius Axelrod, Sol Snyder, and Candace Pertall). It’s one of the best and most incredibly honest accounts of what scientific mentor-protégé relationships are really like. Highly recommended
Brave Genius: A Scientist, a Philosopher, and Their Daring Adventures from the French Resistance to the Nobel Prize. By Sean B. Carroll An amazing account of the story of Jacques Monod and Albert Camus, two friends involved in the French Resistance during the Second World War, and who then went on to produce some of the greatest work in their respective fields (molecular biology and literature)
Ordinary geniuses. How Two Mavericks Shaped Modern Science. By Gino Segre. This enjoyable book tells the story of Max Delbruck and George Gamow, two friends who pioneered some of the most important breakthroughs in molecular biology and physics in the last century.
Laboratory Life. The Construction of Scientific Facts. By Bruno Latour. In this book, Bruno Latour, presents a sociological study of the process of lab research and scientific discovery. Although the study was conducted decades ago, there is a lot to learn from this book on how and why scientific research is organized the way it is. We need more books like this.
Entering an Unseen World. A Founding Laboratory and Origins of Modern Cell Biology (1910-1974) by Carol L Moberg. This enjoyable book describes the history of cell biology told through some of the pioneering discoveries made over the last century at the Rockefeller University
The Molecular Vision of Life. Caltech, the Rockefeller Foundation, and the Rise of the New Biology by Lily E Kay. This books provides an interesting account of a period between the ‘30s and ‘50s when Caltech and the Rockefeller Foundation joined forces to foster the biology that ultimately would lead and inspire to rise of modern genetics and molecular biology. Interestingly, this work had its roots in an early eugenics program supported by the Rockefeller Foundation.
In a recent lab journal club we discussed a paper from the lab of Seung Kim:
A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion. Park S, Alfa RW, Topper SM, Kim GE, Kockel L, Kim SK. (2014) PLoS Genetics, Aug 7;10(8):e1004555.
This paper described a new approach to measure circulating insulins in Drosophila. The authors generated transgenic flies that carry epitope-tagged versions of a drosophila insulin-like peptide (dILP). They then developed an efficient and high- throughput ELISA approach to measure levels of circulating dILP within the hemeolymph of these flies. Using this approach they defined new genes required for controlling dILP release (vs expression). They also showed that changes in circulating dILPs often are not reflected in altered mRNA or protein levels, and that dILP release from neurosecretory cells can be influenced by peripheral insulin signaling.
Measuring circulating dILPs in flies is not straightforward. Many papers have relied on indirect measures (such as dILP mRNA or protein in neurosecretory cells, or assays for downstream insulin/PI3K/FOXO signaling) to infer changes in circulating dILPs. We liked the paper because it provides a powerful new tool to actually measure hemolymph dILP levels. These flies and ELISA assays will help with future studies on the genetic and signaling mechanisms that control insulin function.