Mathematical model of early Reelin-induced Src family kinase-mediated signaling

PLoS One. 2017 Oct 19;12(10):e0186927. doi: 10.1371/journal.pone.0186927. eCollection 2017.

Abstract

Reelin is a large glycoprotein with a dual role in the mammalian brain. It regulates the positioning and differentiation of postmitotic neurons during brain development and modulates neurotransmission and memory formation in the adult brain. Alterations in the Reelin signaling pathway have been described in different psychiatric disorders. Reelin mainly signals by binding to the lipoprotein receptors Vldlr and ApoER2, which induces tyrosine phosphorylation of the adaptor protein Dab1 mediated by Src family kinases (SFKs). In turn, phosphorylated Dab1 activates downstream signaling cascades, including PI3-kinase-dependent signaling. In this work, a mechanistic model based on ordinary differential equations was built to model early dynamics of the Reelin-mediated signaling cascade. Mechanistic models are frequently used to disentangle the highly complex mechanisms underlying cellular processes and obtain new biological insights. The model was calibrated on time-resolved data and a dose-response measurement of protein concentrations measured in cortical neurons treated with Reelin. It focusses on the interplay between Dab1 and SFKs with a special emphasis on the tyrosine phosphorylation of Dab1, and their role for the regulation of Reelin-induced signaling. Model selection was performed on different model structures and a comprehensive mechanistic model of the early Reelin signaling cascade is provided in this work. It emphasizes the importance of Reelin-induced lipoprotein receptor clustering for SFK-mediated Dab1 trans-phosphorylation and does not require co-receptors to describe the measured data. The model is freely available within the open-source framework Data2Dynamics (www.data2dynamics.org). It can be used to generate predictions that can be validated experimentally, and provides a platform for model extensions both to downstream targets such as transcription factors and interactions with other transmembrane proteins and neuronal signaling pathways.

Publication types

  • Validation Study

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cells, Cultured
  • Extracellular Matrix Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Theoretical*
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation
  • Reelin Protein
  • Serine Endopeptidases / metabolism*
  • Signal Transduction*
  • src-Family Kinases / metabolism*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Reelin Protein
  • src-Family Kinases
  • Reln protein, mouse
  • Serine Endopeptidases

Grants and funding

This work was supported by the German Ministry of Education and Research through the grant ReelinSys (e:bio Grant No. 0316174A and C) and by the German Research Foundation (DFG) through the Collaborative Research Center SFB974 (TP B10). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.