The Genetics and Physiology of Growth in Drosophila

Animal growth is a complex process that is intimately linked to the developmental program in order to form adults with proper size and proportions. Genetics is an important determinant of growth, as exemplified by the role of local diffusible molecules in setting organ proportion in a given specie. In addition to this genetic control, organisms use adaptative responses allowing modulating the size of individuals according to environmental cues, among which nutrition. Therefore, a sophisticated crosstalk between local and global cues is at play for the ultimate determination of the size of an individual.

Distinct hormone axes controls the two main parameters that determine final adult size, i.e. the speed of growth, or growth rate, and the duration of growth, which in many species is limited by sexual maturation. In metazoans, the insulin/insulin-like growth factor (IGF) signaling pathway (IIS) controls the growth rate of tissues according to nutrient availability. On the other hand, the clock that runs the developmental transitions and determines the duration of growth is controlled by steroid hormone regulations. Again, important cross-talks exist between these regulations. Our approach to understand this complex orchestration is to utilize the power of a simple genetic metazoan model like Drosophila melanogaster .

Despite 700 million years of evolutionary divergence from mammals, Drosophila has an archetypal insulin/IGF system functionally analogous to the dual mammalian insulin/IGF system (IIS). Insulin-producing cells (IPCs) are brain neurosecretory cells that provide a systemic endocrine signal for the regulation of growth and glucose metabolism, much like pancreatic beta-cells. A large body of work has accumulated over the last years, which demonstrates that all the conserved components of the insulin signaling pathway in the fly are required for organismal growth and metabolic homeostasis.

In vivo studies in flies and other systems have demonstrated that IIS levels are controlled by food availability and specially amino acids. Overall, this supports the idea that IIS co-ordinates tissue growth with nutritional conditions. However, IIS does not respond directly to amino acid levels in cultured cells, suggesting that an independent molecular sensor and/or specific tissues must be dedicated to couple nutrition and growth parameters. The TOR pathway controls nutrient and energy homeostasis in cells ranging from yeast to mammals, and is therefore a candidate pathway for participating in a nutrient sensing mechanism in the larva.

In our recent work, we have explored the possibility that specific organs could function as nutrition sensors and induce a modulation of the main endocrine signals in response to changes in nutrient levels. We demonstrated using a blend of Genetics and Physiology that the larval fat body and the ring gland are such tissues.

The insect fat body (FB) has important storage and humoral functions comparable to those of vertebrate liver. We have shown that suppressing amino acid import in fat body cells turns TOR signaling down in this tissue. This in turn induces general growth inhibition via a remote down-regulation of insulin signaling in peripheral tissues. This work provided the first in vivo evidence for a central nutrition sensor mechanism controlling organismal growth. In parallel to the control of the growth rate through IIS, the duration of the growth period is also controlled by environmental cues. Ecdysone, the main steroid hormone in insects serves as a major developmental clock, setting the time for the developmental transition during insect life. It is produced in an endocrine organ called the ring gland. Our recent work unraveled a mechanism using the TOR pathway to couple ecdysone production with nutrition. By genetically modifying the activity of the TOR pathway specifically in the ring gland, we demonstrated that this organ links nutritional inputs to ecdysone production, therefore controlling the duration of larval development and adult final size.

These studies shed new light on our understanding of the mechanisms allowing coupling the rate and the duration of growth with environmental parameters like nutrition. Yet, the coupling mechanisms are not understood and their elucidation will necessitate focusing on the physiological cross talks between individual tissues like the fat body, the brain and the ring gland.

Another aspect of growth control and size determination has emerged recently with the re-evaluation of classical studies on transplantation and tissue regeneration, raising outstanding questions about the determination of final tissue size, the cessation of growth and the coupling between tissue growth and the developmental program. In insect, adult structures originate from primordia called imaginal discs, which have served as powerful paradigms for the study of organ growth and patterning. Early experiments performed 40 years ago in Drosophila showed that the wounding of imaginal discs, using either genetic, surgical or physical methods, induces regenerative growth until the tissues have recovered their size and shape. Similarly, discs wounded before a certain stage of development induce a delay to pupariation, allowing the wounded tissue to regenerate before metamorphosis. In contrast, the complete ablation of imaginal discs has no effect on the developmental timing. These simple but insightful experiments support two important conclusions: (i) imaginal discs are subjected to an autonomous growth program allowing to reach their final size independently of the developmental stage of the host; (ii) a signal released from growing imaginal discs acts on the host to prevent the onset of metamorphosis until growth, patterning and maturation of the discs is complete. Deciphering the mechanisms controlling final tissue size and the cross-talk with the developmental clock represent essential and timely goals for our understanding of the physiology of growth. The existence of advanced concepts and the mastering of sophisticated genetic tools in Drosophila make it a particularly attractive model to ask these questions.

The primary goal of our projects is to use Drosophila Genetics to decipher the Physiology of the coupling between Development, Environment and the Growth program that together determine the final size of an organism. Our specific aims are the following

- aim 1: understanding how insulin signaling is modulated by the nutrition sensor, and in particular identifying the humoral connection between the tissues involved in sensing the nutrients and those producing insulin-like peptides.

- aim 2: understanding the molecular basis for tissue growth arrest and the coordination between tissue growth and the developmental timing.


Last publications

Drosophila insulin release is triggered by adipose Stunted ligand to brain Methuselah receptor. - 2016 - Science (New York, N.Y.) - 353 P1553-1556 - Delanoue R, Meschi E, Agrawal N, Mauri A, Tsatskis Y, McNeill H, and Léopold,P

The Hippo signalling pathway coordinates organ growth and limits developmental variability by controlling dilp8 expression. - 2016 - Nature communications - 7 P13505 - Boone E, Colombani J, Andersen DS, and Léopold,P

The Drosophila TNF Eiger Is an Adipokine that Acts on Insulin-Producing Cells to Mediate Nutrient Response. - 2016 - Cell metabolism - 23 P675-84 - Agrawal N, Delanoue R, Mauri A, Basco D, Pasco M, Thorens B, and Léopold,P

Drosophila Lgr3 Couples Organ Growth with Maturation and Ensures Developmental Stability. - 2015 - Current biology : CB - 25 P2723-2729 - Colombani J, Andersen DS, Boulan L, Boone E, Romero N, Virolle V, Texada M, and Léopold,P

The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. - 2015 - Nature - Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Rì¶thlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, and Léopold,P

Sensing of amino acids in a dopaminergic circuitry promotes rejection of an incomplete diet in Drosophila. - 2014 - Cell - 156 P510-21 - Bjordal M, Arquier N, Kniazeff J, Pin JP, and Léopold,P

Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. - 2012 - Science - 336 P582-5 - Colombani J, Andersen DS, and Léopold,P

High sugar-induced insulin resistance in Drosophila relies on the lipocalin Neural Lazarillo. - 2012 - PLoS One - 7 Pe36583 - Pasco MY, and Léopold,P

The steroid hormone ecdysone controls systemic growth by repressing dMyc function in Drosophila fat cells. - 2010 - Dev Cell - 18 P1012-21 - Delanoue R, Slaidina M, and Léopold,P

Remote control of insulin secretion by fat cells in Drosophila. - 2009 - Cell Metab - 10 P199-207 - Géminard C, Rulifson EJ, and Léopold,P

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Léopold Pierre
Group Leader

2015 ERC Advanced grant

2014 Prix Académie des Sciences/AXA à M. Bjordal

2011 Prix Recherche Inserm

2010 ERC Advanced grant

2009 Prix Jules Martin de Académie des Sciences

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Members Team
   Andersen Ditte
   Arquier Nathalie
   Bourouis Marc
   Colombani Julien
   Delanoue Renald
   Romero Nuria
   Bjordal Marianne
   Boulan Laura
   Deveci Derya
   Meschi Eleonora
Engineers & Technicians
   Pihl Thomas
Photos ...

    November 2016 - P. Leopold Team
   1 CDD Technicien AI Biologiste 5 ans

    September 2009 - P.Leopold Team
   1 POST-DOC Position 3 ans   Closed



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