title: How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex.
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.
authors.affiliation: Computational Science Laboratory, Microsoft Research, Cambridge, CB3 0FB, UK. yaki.setty@gmail.com
authors.forename: Yaki
authors.initials: Y
authors.lastname: Setty
authors.forename: Chih-Chun
authors.initials: CC
authors.lastname: Chen
authors.forename: Maria
authors.initials: M
authors.lastname: Secrier
authors.forename: Nikita
authors.initials: N
authors.lastname: Skoblov
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kalamatianos
authors.forename: Stephen
authors.initials: S
authors.lastname: Emmott
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology* / Q000254:growth & development; D002465:Cell Movement; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051381:Rats; D000091042:Reelin Protein; D049490:Systems Biology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C000714847:Dcx protein, mouse; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C516550:Pafah1b1 protein, rat; D000091042:Reelin Protein; C000717129:Reln protein, rat; D005680:gamma-Aminobutyric Acid; C000717128:Reln protein, mouse