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1.
Curr Biol ; 11(4): 213-21, 2001 Feb 20.
Article in English | MEDLINE | ID: mdl-11250149

ABSTRACT

BACKGROUND: Size regulation is fundamental in developing multicellular organisms and occurs through the control of cell number and cell size. Studies in Drosophila have identified an evolutionarily conserved signaling pathway that regulates organismal size and that includes the Drosophila insulin receptor substrate homolog Chico, the lipid kinase PI(3)K (Dp110), DAkt1/dPKB, and dS6K. RESULTS: We demonstrate that varying the activity of the Drosophila insulin receptor homolog (DInr) during development regulates organ size by changing cell size and cell number in a cell-autonomous manner. An amino acid substitution at the corresponding position in the kinase domain of the human and Drosophila insulin receptors causes severe growth retardation. Furthermore, we show that the Drosophila genome contains seven insulin-like genes that are expressed in a highly tissue- and stage-specific pattern. Overexpression of one of these insulin-like genes alters growth control in a DInr-dependent manner. CONCLUSIONS: This study shows that the Drosophila insulin receptor autonomously controls cell and organ size, and that overexpression of a gene encoding an insulin-like peptide is sufficient to increase body size.


Subject(s)
Conserved Sequence/physiology , Drosophila/growth & development , Evolution, Molecular , Insect Proteins/physiology , Insulin/physiology , Peptides/physiology , Receptor, IGF Type 1/physiology , Receptor, Insulin/physiology , Amino Acid Sequence , Amino Acids , Animals , Animals, Genetically Modified , Binding Sites , Cell Count , Cell Division , Cell Size , Drosophila/genetics , Drosophila/metabolism , Gene Expression , Gene Expression Regulation , Genes, Insect , Humans , Insect Proteins/genetics , Insect Proteins/metabolism , Insulin/genetics , Insulin/metabolism , Molecular Sequence Data , Mutagenesis , Peptides/genetics , Peptides/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/physiology , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Receptor, Insulin/genetics , Receptor, Insulin/metabolism
2.
Philos Trans R Soc Lond B Biol Sci ; 355(1399): 945-52, 2000 Jul 29.
Article in English | MEDLINE | ID: mdl-11128988

ABSTRACT

During the past ten years, significant progress has been made in understanding the basic mechanisms of the development of multicellular organisms. Genetic analysis of the development of Caenorhabditis elegans and Drosophila has unearthed a fruitful number of genes involved in establishing the basic body plan, patterning of limbs, specification of cell fate and regulation of programmed cell death. The genes involved in these developmental processes have been conserved throughout evolution and homologous genes are involved in the patterning of insect and human limbs. Despite these important discoveries, we have learned astonishingly little about one of the most obvious distinctions between animals: their difference in body size. The mass of the smallest mammal, the bumble-bee bat, is 2 g while that of the largest mammal, the blue whale, is 150 t or 150 million grams. Remarkably, even though they are in the same class, body size can vary up to 75-million-fold. Furthermore, this body growth can be finite in the case of most vertebrates or it can occur continuously throughout life, as for trees, molluscs and large crustaceans. Currently, we know comparatively little about the genetic control of body size. In this article we will review recent evidence from vertebrates and particularly from Drosophila that implicates insulin/insulin-like growth factor-I and other growth pathways in the control of cell, organ and body size.


Subject(s)
Drosophila/growth & development , Drosophila/genetics , Animals , Humans
3.
Development ; 126(23): 5365-72, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10556061

ABSTRACT

Mutations in the tumor suppressor gene PTEN (MMAC1/TEP1) are associated with a large number of human cancers and several autosomal-dominant disorders. Mice mutant for PTEN die at early embryonic stages and the mutant embryonic fibroblasts display decreased sensitivity to cell death. Overexpression of PTEN in different mammalian tissue culture cells affects various processes including cell proliferation, cell death and cell migration. We have characterized the Drosophila PTEN gene and present evidence that both inactivation and overexpression of PTEN affect cell size, while overexpression of PTEN also inhibits cell cycle progression at early mitosis and promotes cell death during eye development in a context-dependent manner. Furthermore, we have shown that PTEN acts in the insulin signaling pathway and all signals from the insulin receptor can be antagonized by either Drosophila or human PTEN, suggesting a potential means for alleviating symptoms associated with altered insulin signaling.


Subject(s)
Apoptosis/genetics , Drosophila/genetics , Eye/embryology , Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/metabolism , Tumor Suppressor Proteins , Amino Acid Sequence , Animals , Cell Division/genetics , Cell Size/genetics , Cloning, Molecular , Eye/cytology , G1 Phase/genetics , Gene Expression Profiling , Gene Expression Regulation, Developmental , Genes, Tumor Suppressor , Humans , Insect Proteins/genetics , Insect Proteins/metabolism , Insulin/metabolism , Larva , Molecular Sequence Data , PTEN Phosphohydrolase , Receptor, Insulin/metabolism , S Phase/genetics , Sequence Homology, Amino Acid , Signal Transduction
4.
Cell ; 97(7): 865-75, 1999 Jun 25.
Article in English | MEDLINE | ID: mdl-10399915

ABSTRACT

The control of growth is fundamental to the developing metazoan. Here, we show that CHICO, a Drosophila homolog of vertebrate IRS1-4, plays an essential role in the control of cell size and growth. Animals mutant for chico are less than half the size of wild-type flies, owing to fewer and smaller cells. In mosaic animals, chico homozygous cells grow slower than their heterozygous siblings, show an autonomous reduction in cell size, and form organs of reduced size. Although chico flies are smaller, they show an almost 2-fold increase in lipid levels. The similarities of the growth defects caused by mutations in chico and the insulin receptor gene in Drosophila and by perturbations of the insulin/IGF1 signaling pathway in vertebrates suggest that this pathway plays a conserved role in the regulation of overall growth by controling cell size, cell number, and metabolism.


Subject(s)
Carrier Proteins , Drosophila Proteins , Insect Proteins/metabolism , Intracellular Signaling Peptides and Proteins , Receptor, Insulin/metabolism , Amino Acid Sequence , Animals , Apoptosis , Body Constitution , Cell Count , Cell Size , Drosophila/genetics , Drosophila/metabolism , Drosophila/physiology , Female , Insect Proteins/genetics , Insulin Receptor Substrate Proteins , Lipid Metabolism , Male , Molecular Sequence Data , Mutagenesis , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Receptor, Insulin/genetics , Sequence Homology, Amino Acid , Vertebrates
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