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The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP₃ levels

¹ Universität Zürich, Zoologisches Institut, Winterthurerstrasse 190, CH – 8057, Zürich, Switzerland
² Université de Fribourg, Institute de Biochemie, Rue du Musée 5, CH – 1700, Fribourg, Switzerland

View larger version (27K): [in a new window]   Fig. 1. Chico PH, PTB, Drk, and PI 3-kinase effector mutants. (A) The chico genomic rescue construct and the corresponding PH, PTB, Drk, and PI 3-kinase effector consensus site mutants. Numbers indicate amino acid positions (not drawn to scale). (B) The PI 3-kinase, PH and PTB consensus sites are critically required for Chico function in body size control, while the Drk consensus site is dispensable. The weight of male flies carrying the various transgenes was measured as described by Böhni et al. (Böhni et al., 1999). (C) The PTB domain is not required for Chico control of female fertility. The number of pupae that developed from eggs laid by an equal number of females of the indicated genotype is shown. (D) All the Chico effectors, except Drk, function in the control of lipid metabolism. All assays were performed three times on at least 10 flies.

View larger version (84K): [in a new window]   Fig. 2. Loss of PTEN function rescues InR null mutations. (A) Pten2L117/Pten2L100 mutant larvae have increased PtdInsP3 levels. Data are presented as PtdInsP3:PtdInsP2 ratios and are standardized to the wild-type y w control. The experiment was performed twice with quantitatively similar results. (B) The Pten2L117/Pten2L100 mutant larva (top) is increased in size compared to the y w control. (C) Scanning electromicrograph (SEM) of a dorsal view of a y w control fly. Bar (above C) is 200 µm in all cases. (D) Loss of PTEN function (Pten2L117/Pten2L117) selectively in the head using the eyFlp system (Newsome et al., 2000) results in the overproliferation of the head. (E) Loss of InR function (InR327/InR327) selectively in the head using the eyFlp system results in a pinhead. (F) Concomitant loss of InR and PTEN function (Pten2L117/Pten2L117; InR327/InR327) in the head is sufficient to suppress the growth and proliferation defect associated with InR single mutants. (G) The 2nd instar lethality associated with the InR304/InR327 allelic combination is rescued to the pharate adult stage in the Pten2L117/Pten2L100; InR304/InR327 double mutant combination (left). (Right) A y w control. (H) The frequency of rescue to the pupal stage of InR304/InR327 (InR1) (n=15 crosses) and InR304/InR25 (InR2) (n=5 crosses) by the partial loss-of-function Pten2L117/Pten2L100 combination. ‘Expected’ denotes the expected Mendelian frequency for complete rescue to the pupal stage for the genotype: y w; Pten2L117/Pten2L100; InR304/InR327 from the cross (y w; Pten2L117; InR304/Cyo^TM6B x y w; Pten2L100; InR327/Cyo^TM6B).

View larger version (137K): [in a new window]   Fig. 3. PtdInsP3 levels control the range of growth and size. (A) Quantification of the eye size of the various mutants. Measurements were made from SEM images by calculating the longest distance of a side view of the eye from dorsal to ventral plus anterior to posterior (n=4-7). The same pattern was also seen when head:thorax ratios were determined from a dorsal view (data not shown). (B) Dorsal view SEM of a y w control fly. Bar above C is 200 µm in all cases. (C) Selective loss of PI 3-kinase p110 function in the head using the eyFlp system results in a strong pinhead phenotype. (D) Loss of PTEN function cannot rescue complete loss of PI 3-kinase p110 function in mosaic clones. The genotype of the fly head shown is Pten2L117/Pten2L117; PI 3-kinasenull/PI 3-kinasenull. (E) Selectively loss of PI 3-kinase p60 function in the head using the eyFlp system results in a strong pinhead phenotype. (F) Loss of PTEN function rescues to wild-type size complete loss of Pi3K p60 function in mosaic clones. The genotype of the fly head shown is Pten2L117/Pten2L117; PI3K p60null/Pi3Kp60null.

View larger version (47K): [in a new window]   Fig. 4. Pten regulates size, metabolism and survival in an opposite manner to positive components of the insulin pathway like Chico. (A) A Pten2L117/Pten2L100 mutant fly (right) compared to the y w control (left). (B) Pten2L117/Pten2L100 mutant flies weigh more than the y w control (data not shown) or to Pten mutants rescued with the Pten genomic rescue construct (n=10). (C) Pten2L117/Pten2L100 mutant flies have decreased glycogen and lipids compared to the y w control (data not shown) or to Pten mutants rescued with the Pten genomic rescue construct (n=10). The glycogen data are transformed by one log10 power. (D) Pten2L117/Pten2L100 mutant flies are hypersensitive to water-only starvation conditions compared to a starvation resistant chico1/chico1 mutant. All assays were performed at least 2 times independently.

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