Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression

Cell Death Differ. 2007 Jun;14(6):1095-105. doi: 10.1038/sj.cdd.4402109. Epub 2007 Mar 2.

Abstract

Although much is known about the global effects of insulin-like growth factor 1 receptor (IGF1R)-mediated signaling on fetal growth and the clinical manifestations resulting from IGF/IGF1R deficiencies, we have an incomplete understanding of the cellular actions of this essential pathway during vertebrate embryogenesis. In this study, we inhibited IGF1R signaling during zebrafish embryogenesis using antisense morpholino oligonucleotides or a dominant-negative IGF1R fusion protein. IGF1R inhibition resulted in reduced embryonic growth, arrested development and increased lethality. IGF1R-deficient embryos had significant defects in the retina, inner ear, motoneurons and heart. No patterning abnormalities, however, were found in the brain or other embryonic tissues. At the cellular level, IGF1R inhibition increased caspase 3 activity and induced neuronal apoptosis. Coinjection of antiapoptotic bcl2-like mRNA attenuated the elevated apoptosis and rescued the retinal and motoneuron defects, but not the developmental arrest. Subsequent cell cycle analysis indicated an increased percentage of cells in G1 and a decreased percentage in S phase in IGF1R-deficient embryos independent of apoptosis. These results provide novel insight into the cellular basis of IGF1R function and show that IGF1R signaling does not function as an anteriorizing signal but regulates embryonic growth and development by promoting cell survival and cell cycle progression.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Blotting, Western
  • Body Patterning / genetics
  • Body Patterning / physiology
  • Caspase 3 / metabolism
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Flow Cytometry
  • Gene Expression Regulation, Developmental / drug effects
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Hybridization
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / physiology
  • Neurons / cytology
  • Neurons / metabolism
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / pharmacology
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Zebrafish / embryology*
  • Zebrafish / genetics

Substances

  • Oligonucleotides, Antisense
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Caspase 3