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Developmental Toxicity Assay Based on Real-Time Monitoring of Fibroblast Growth Factor Signal Disruption in Human Induced Pluripotent Stem Cells
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Developmental Toxicity Assay Based on Real-Time Monitoring of Fibroblast Growth Factor Signal Disruption in Human Induced Pluripotent Stem Cells

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Development of a Whole Organism Platform for Phenotype-Based Analysis of IGF1R-PI3K-Akt-Tor Action

Chengdong Liu1,2, Wei Dai2,3, Yan Bai2

  • 1The Key Laboratory of Mariculture, Education Ministry of China and College of Fisheries, Ocean University of China, Qingdao, 266003, China.

Scientific Reports
|May 19, 2017
PubMed

Insights

We developed a zebrafish model to study the insulin-like growth factor (IGF) signaling pathway in real-time. This whole-organism platform aids in discovering new therapeutic targets for diseases linked to this pathway.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Signaling Pathways

Background:

  • Aberrant regulation of the insulin-like growth factor (IGF)/insulin (IIS)-PI3K-AKT-TOR signaling pathway is implicated in major human diseases.
  • Existing molecular or cell culture-based assays lack the in vivo complexity needed to fully understand this pathway.
  • There is a significant need for whole-organism assays to study IIS-PI3K-AKT-TOR signaling dynamics.

Purpose of the Study:

  • To develop a novel zebrafish transgenic line for real-time, whole-organism analysis of the IIS-PI3K-AKT-TOR signaling pathway.
  • To establish a high-throughput platform for studying epithelial cell proliferation and cell cycle dynamics in vivo.
  • To enable phenotype-based discovery of novel pathway components and therapeutic inhibitors.

Main Methods:

  • Development of a zebrafish transgenic line, Tg(igfbp5a:GFP), to report mitotic activity of the IGF1R-PI3K-Akt-Tor signaling pathway.
  • Utilizing the Tg(igfbp5a:GFP) line for high-throughput screening and real-time cell cycle analysis.
  • Investigating epithelial cell proliferation dynamics under low calcium stress and elucidating the roles of Torc1 and Torc2.

Main Results:

  • The Tg(igfbp5a:GFP) zebrafish line accurately reports IIS-PI3K-AKT-TOR signaling-driven mitotic activity in epithelial cells in real-time.
  • The platform facilitates high-throughput assays and detailed cell cycle analysis within a whole organism context.
  • Distinct roles of Torc1 and Torc2 in epithelial cell proliferation under low calcium stress were elucidated.

Conclusions:

  • The Tg(igfbp5a:GFP) zebrafish line offers a powerful whole-organism platform for studying the IIS-PI3K-AKT-TOR pathway.
  • This model system is suitable for the discovery of novel pathway regulators and potential therapeutic interventions.
  • The platform advances in vivo research for diseases associated with dysregulated IGF/insulin signaling.

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