Setty, Yaki and Chen, Chih-Chun and Secrier, Maria and Skoblov, Nikita and Kalamatianos, Dimitrios and Emmott, Stephen (2011) How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex. BMC Systems Biology, 5 (154). pp. 1-13. ISSN 1752-0509

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Abstract

Background: Neuronal migration, the process by which neurons migrate from their place of origin to their final position in the brain, is a central process for normal brain development and function. Advances in experimental techniques have revealed much about many of the molecular components involved in this process. Notwithstanding these advances, how the molecular machinery works together to govern the migration process has yet to be fully understood. Here we present a computational model of neuronal migration, in which four key molecular entities, Lis1, DCX, Reelin and GABA, form a molecular program that mediates the migration process. Results: The model simulated the dynamic migration process, consistent with in-vivo observations of morphological, cellular and population-level phenomena. Specifically, the model reproduced migration phases, cellular dynamics and population distributions that concur with experimental observations in normal neuronal development. We tested the model under reduced activity of Lis1 and DCX and found an aberrant development similar to observations in Lis1 and DCX silencing expression experiments. Analysis of the model gave rise to unforeseen insights that could guide future experimental study. Specifically: (1) the model revealed the possibility that under conditions of Lis1 reduced expression, neurons experience an oscillatory neuron-glial association prior to the multipolar stage; and (2) we hypothesized that observed morphology variations in rats and mice may be explained by a single difference in the way that Lis1 and DCX stimulate bipolar motility. From this we make the following predictions: (1) under reduced Lis1 and enhanced DCX expression, we predict a reduced bipolar migration in rats, and (2) under enhanced DCX expression in mice we predict a normal or a higher bipolar migration. Conclusions: We present here a system-wide computational model of neuronal migration that integrates theory and data within a precise, testable framework. Our model accounts for a range of observable behaviors and affords a computational framework to study aspects of neuronal migration as a complex process that is driven by a relatively simple molecular program. Analysis of the model generated new hypotheses and yet unobserved phenomena that may guide future experimental studies. This paper thus reports a first step toward a comprehensive in-silico model of neuronal migration.

Item Type:	Article
Additional Information:	The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1752-0509/5/154 . © 2011 Setty et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords:	neurons; dynamic; in-silico; model; neuronal migration; developing cortex; brain development;
Academic Unit:	Faculty of Science and Engineering > Research Institutes > Hamilton Institute
Item ID:	3636
Depositing User:	Dimitris Kalamatianos
Date Deposited:	08 May 2012 14:57
Journal or Publication Title:	BMC Systems Biology
Publisher:	BioMed Central
Refereed:	Yes
URI:	http://www.biomedcentral.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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