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.
Highlights
Reelin plays a pivotal role in brain development
To obtain a mathematical model of Reelin-induced Dab1 and Src family kinase (SFK) activation, we performed model selection based on two different hypotheses
In the first model, defined as ‘monomer’ model (Fig 3A), binding of Reelin to its canonical receptors leads to tyrosine phosphorylation of Dab1 [41,42,43]
Summary
Reelin plays a pivotal role in brain development. Reelin is secreted by Cajal-Retzius cells, a specialized cell population in the developing central nervous system (CNS), which coordinates migration of postmitotic neurons in laminar structures of the brain like hippocampus, neocortex and cerebellum. The autosomal recessive mutant mouse reeler [1] underlines the importance of Reelin. Affected mice are characterized by ataxic behavior and display multiple defects in the CNS such as cerebellar hypoplasia and impaired cortical lamination [1]. An association between altered Reelin expression/signaling and several psychiatric and neurological disorders including Alzheimer disease, autism, major depression, schizophrenia, and temporal lobe epilepsy has been demonstrated [2,3,4,5]. The precise contribution of Reelin signaling events in this context remains unclear
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