Lab Journal Club: Sex, guts (and rock & roll)

Image from Hudry et al, Nature (2016)

Image from Hudry et al, Nature (2016)

In our last journal club we discussed two very nice papers on sexual dimorphism in Drosophila intestines that controls growth, regeneration and lifespan:

The sexual identity of adult intestinal stem cells controls organ size and plasticity. Hudry B, Khadayate S, Miguel-Aliaga I. Nature. 2016 Feb 18;530(7590):344-8

Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction. Regan JC, Khericha M, Dobson AJ, Bolukbasi E, Rattanavirotkul N, Partridge L. Elife. 2016 Feb 16;5. pii: e10956.

In the first paper, Bruno Hudry (from the lab of Irene Miguel Aliaga) showed that female intestines showed both a marked increase in cell proliferation/regeneration in response to damage and in increase propensity to develop tumors. Both these effects were dependent on the sexual identity of the intestinal stem cells, which is controlled by Transformer expression.

The second paper from Jenny Regan described male:female differences in both intestinal pathology in aged guts and response to infection. Interestingly, this paper indicates that these differences are regulated by the sexual identity of the differentiated epithelial cells in the gut, although the differences do involve altered stem cell proliferation.

 We liked both papers a lot. Its a topic that we’ve become interested in – our former postdoc, Liz Rideout, recently published a paper on sex differences in insulin signaling and growth in Drosophila, and she’s continuing this work in her own lab at UBC.

Lab Journal Club: Growth Blocking Peptides, insulin signaling and control of body size in flies

UntitledIn a recent lab journal club we discussed a very nice paper from Takashi Koyama and Christen Mirth:

Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation. (2016) PLoS Biology

Nutrients promote body growth in Drosophila by stimulating insulin signaling. One main way that this happens involves endocrine signaling between the fat body and the brain – in protein rich diets, amino acid import into fat body cells activates TOR and leads to release of a secreted factor(s) that acts on the brain to stimulate expression and release of insulin-like peptides (ILPs) from neurosecretory cells. However, the nature of the these AA-sensitive fat body factors has remained elusive. In this paper, the authors identify the Growth Blocking Peptides 1 and 2 (GBP1 and 2) as strong candidates. They show that expression of GBP1 and 2 is regulated by AA/TOR signaling and that both GBP1 and 2 are secreted from the fat body and can act directly on the brain to promote ILP release.

We liked this paper a lot. In particular we appreciated the rigorous and comprehensive approach the authors used to establish that both GBP1 and 2 are bona fide fat-body derived factors that respond to TOR signaling and that act directly on the brain to promote insulin release.

Lab Journal Club: nutrients, TOR, gene expression and lifespan

CD_Fruitfly03Last week in lab journal club we discussed a very nice paper by @mattpiperlab and @a_j_dobson available online on bioRxiv:

Lifespan extension by dietary restriction in Drosophila is associated with GATA motifs and organ-specific, TOR-dependent transcriptional networks.

Dietary restriction of amino acids and inhibition of TOR (by Rapamycin) are two robust ways to extend lifespan in flies. Here the authors do some very nice tissue mRNA expression analyses to examine how these two experimental manipulations may affect gene expression. Their data reveal some interesting tissue specific effects in transcription and also point to a role for GATA transcription factors in lifespan-associated transcriptional changes.

We liked this paper – it will open up lots of new work on GATA factors and nutrient/TOR signaling.  And we were especially happy to see it on bioRXiv for all to view. Some thoughts we had (mostly for future work): Does TOR signaling regulate the GATA transcription factors? Do these GATA factors regulate lifespan? Might they also be important for nutrient/TOR control of transcription and growth in larvae or do nutrients/TOR regulate two different transcriptional programs in larvae (growth) vs adult (fecundity and lifespan)?

Lab Journal Club: nutritional control of insulin expression in flies

UntitledThis week we discussed the following paper:

Signaling from Glia and Cholinergic Neurons Controls Nutrient-Dependent Production of an Insulin-like Peptide for Drosophila Body Growth (2015) Dev Cell, 35, 295

Naoki Okamoto and Takashi Nishimura


In this paper Okamoto and Nishimra describe how dILP5 mRNA expression is regulated by dietary nutrients (protein). This regulation relies on a relay mechanism involving nutrient-responsive glia, which locally secrete dILP6 to activate cholinergic neurons, which then secrete Jeb that activated the Alk receptor on the surface of IPCs, which then induce dILP5 expression in response to PI3K/Akt activation.

We liked this paper. We were interested in some of the parallels between how IPCs responded to nutrients to control dILP5 and how neuroblasts control their division in response to nutrients (in papers we have discussed in previous lab journal clubs). In both cases, an initial step is local dILP6 secretion from surface glia, however, in the case of neuroblast division, these glia respond to a fat-derived signal release in response to TOR activation (Chell, 2010; Sousa-Nunes, 2011). In this paper, activation of TOR in the fat body appears to be unnecessary. Instead the surface glia respond directly to amino acids and insulins. Similarly the Jeb-ALK pathway is also involved in controlling IPCs in neuroblasts. In this paper, ALK activation of IPCs is necessary to promote dILP5 expression in nutrient-rich conditions. In contrast ALK activation of neuroblasts is required to maintain their proliferation in late larval starvation (brain sparing – Cheng, 2011)

Lab Journal Club: Synchronizing organ growth and developmental timing

CD_Fruitfly01This 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.

Vallejo DM, Juarez-Carreño S, Bolivar J, Morante J, Dominguez M. A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3. Science. 2015 Nov 13;350(6262)

The relaxin receptor Lgr3 mediates growth coordination and developmental delay during Drosophila melanogaster imaginal disc regeneration. (2015) BioRxiv. Jacob S. Jaszczak, Jacob B. Wolpe, Rajan Bhandari, Rebecca G. Jaszczak, Adrian Halme




Recent lab journal clubs: flies, insulin, TOR and other good stuff


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.

Lab Journal Club: New ways to control translation and growth in flies

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.Schleich S, Strassburger K, Janiesch PC, Koledachkina T … Küchler K, Stoecklin G, Duncan KE, Teleman AA.  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.

Lab Journal club: tuning tRNA levels to control gene expression

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.Gingold H, Tehler D, Christoffersen NR, Nielsen MM … Dahan O, Pedersen JS, Lund AH, Pilpel Y.  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 (Pavon-Eternod et al 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.

Lab journal club: measuring circulating insulins in flies

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.

This weeks lab journal club: nutrient and neuronal contol of tracheal branching

In a recent lab journal club, we discussed a recent paper from the Miguel-Aliaga lab:

Neuronal Control of Metabolism through Nutrient-Dependent Modulation of Tracheal Branching, 2014, Cell, 156, 69.

In this paper, the Miguel-Aliaga group show that nutrient rich conditions promote tracheal branching in the larval, especially the gut, whereas upon starvation this branching is reduced . This control of branching relies on both systemic insulin signaling and also local signaling to trachea via VIP- and insulin-secreting neurons, whose activity is regulated by dietary nutrients. Moreover, the starvation effects on branching could mimicked by genetically inhibiting the insulin/PI3K pathway in tracheal termini (we wondered whether cell-autonomous overexpression of insulin/PI3K signaling could also promote branching, especially in starved animals)

We really liked this paper: Another great example of how the simplicity and versatility of fly genetics can be used to unravel important cell-to-cell and tissue-to-tissue signaling mechanisms that govern whole animal physiology.