Secreted peptide dilp8 coordinates Drosophila tissue growth with developmental timing
(J. Colombani et al., Science 336, 2012)
Drosophila melanogaster is a model organism for research on developmental processes, such as
morphogenesis. Regeneration experiments have shown that defects in larval tissue growth result in
delayed metamorphosis. Therefore a certain mechanism has to exist which mediates sensing of such
perturbations and adjusts developmental timing. Involved molecules are still unknown. The authors of
the publication carried out a genetic screen to identify participating molecules. They were able to show
that dilp8 secretion is sufficient for developmental delay upon tissue growth impairment. They conclude
dilp8 to be induced in damaged larval tissues to gain extra time for tissue repair and regenerative growth
by delaying following steps of development.
Molecules contributing to the transduction of the growth status of larval tissues (so-called imaginal discs)
to developmental processes are still unheard-of. To identify these, RNA interference (RNAi) experiments
were carried out. Two tester lines which showed robust developmental delay upon disc growth
alterations were established. For this purpose they used the rotund-Gal4-driver (Rn>) to induce disc
specific down-regulation of targeted genes. Silencing the genes for avalanche (avl) or the ribosomal
protein L7 (rpl7) induced retarded larva-to pupa- transition. In a genome-wide approach different RNAi
lines were investigated regarding their ability to rescue the delayed pupariation. Only one RNA
counteracted the retardation in both tester lines. It targets the CG14059 gene, which encodes an insulinlike peptide (Drosophila insulin-like peptide 8). Quantitative Real-Time PCR revealed up-regulation of
dilp8 upon different growth perturbations. C-Jun N-terminal kinase- (JNK-) pathway was induced in both
tester lines, as shown by puc-lacZ-reporter assays. Reduction of JNK activity led to suppressed dilp8upregulation. Moreover the expression of two hormones which are necessary for metamorphosis was
altered. In both tester lines as well as in lines which expressed dilp8 ectopically in the discs the
prothoracicotropic hormone (PTTH) and ecdysone expression was delayed or abolished, respectively.
Regarding the synthesis of these hormones in the cerebral ring gland and a sequence motif of the
peptide which predicts secretion of dilp8 the authors verified this expectation. Therefore
immunoprecipitation analysis and experiments with dilp8-peptides, lacking the secretion signal were
conducted. Besides co-culture of wildtype and truncated versions of dilp8 with brain complexes showed
that ecdysone is a direct target of the secreted peptide. Based on this data the model illustrated in figure
1 is suggested.
The aim of this study was to identify the molecule which is responsible for relaying growth status of discs
to regulators of metamorphosis. The results indicate that tissue damage leads to activation of JNKpathway which enhances dilp8 expression. Following the peptide is secreted und suppresses ecdysone
production in the ring gland. Ecdysone is needed for the larva-to-pupa transition. So, dilp8 expression
prevents onset of pupariation, thereby delaying subsequent metamorphosis. The involved JNK is known
to be induced upon various forms of tissue stress. Dilp8 expression also varies during normal
development, but regulators of dilp8 activity in healthy discs are still unknown. To gain further
information on this complex network, literature research (with regard to these new findings) as well as
further studies are required. For example, a study called “Retinoids regulate a developmental checkpoint
for tissue regeneration in Drosophila” (A. Halme et al., Curr. Biol. 20, 2010) could provide further
information.
figure 1: suggested model to explain delayed metamorphosis upon impairment of larval tissue growth.
legend: arrows = stimulation, lines ending in a vertical line (˧) = inhibition, interrupted ˧ = delayed
expression, dotted line = some steps have been skipped; JNK = C-Jun N-terminal kinase- pathway; γ-IR =
gamma irradiation. Note that secretion of dilp8 which gets induced in imaginal tissues is necessary for its
influence on brain and ring gland.