Regulation of neurogenesis and epidermal growth factor receptor signaling by the insulin receptor/target of rapamycin pathway in Drosophila

Genetics. 2008 Jun;179(2):843-53. doi: 10.1534/genetics.107.083097. Epub 2008 May 27.

Abstract

Determining how growth and differentiation are coordinated is key to understanding normal development, as well as disease states such as cancer, where that control is lost. We have previously shown that growth and neuronal differentiation are coordinated by the insulin receptor/target of rapamycin (TOR) kinase (InR/TOR) pathway. Here we show that the control of growth and differentiation diverge downstream of TOR. TOR regulates growth by controlling the activity of S6 kinase (S6K) and eIF4E. Loss of s6k delays differentiation, and is epistatic to the loss of tsc2, indicating that S6K acts downstream or in parallel to TOR in differentiation as in growth. However, loss of eIF4E inhibits growth but does not affect the timing of differentiation. We also show, for the first time in Drosophila, that there is crosstalk between the InR/TOR pathway and epidermal growth factor receptor (EGFR) signaling. InR/TOR signaling regulates the expression of several EGFR pathway components including pointedP2 (pntP2). In addition, reduction of EGFR signaling levels phenocopies inhibition of the InR/TOR pathway in the regulation of differentiation. Together these data suggest that InR/TOR signaling regulates the timing of differentiation through modulation of EGFR target genes in developing photoreceptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Drosophila / genetics
  • Drosophila / growth & development
  • Drosophila / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / physiology*
  • Epistasis, Genetic
  • ErbB Receptors / genetics
  • ErbB Receptors / physiology*
  • Eye Proteins / genetics
  • Eye Proteins / physiology
  • Genes, Insect
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / physiology
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Neuropeptides / genetics
  • Neuropeptides / physiology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Photoreceptor Cells, Invertebrate / growth & development
  • Photoreceptor Cells, Invertebrate / physiology
  • Protein Kinases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology
  • Ras Homolog Enriched in Brain Protein
  • Receptor, Insulin / genetics
  • Receptor, Insulin / physiology*
  • Retina / growth & development
  • Retina / physiology
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcription Factors / genetics
  • Transcription Factors / physiology

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Eye Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Proto-Oncogene Proteins
  • Ras Homolog Enriched in Brain Protein
  • Rheb protein, Drosophila
  • Transcription Factors
  • pnt protein, Drosophila
  • aos protein, Drosophila
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • target of rapamycin protein, Drosophila
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • Receptor, Insulin
  • Monomeric GTP-Binding Proteins