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How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex.

Setty Y, Chen CC, Secrier M, Skoblov N, Kalamatianos D, Emmott S - BMC Syst Biol (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Science Laboratory, Microsoft Research, Cambridge, CB3 0FB, UK. yaki.setty@gmail.com

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.

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Normal neuronal migration in the mammalian cortex. A. Snapshots of the neuronal migration simulation. Radial progenitor glial cells (pink) proliferate asymmetrically giving rise to neuroblasts (red). Neuroblasts migrate radially on the glial fiber. Neuroblasts adopt a multipolar stage (green) and migrate independently from the glial fiber. Multipolar neurons re-associate with the glial fiber, enter the bipolar migration (yellow) and accumulate on the pile surface. B. Histology of the mouse cortex at embryonic day 16 (reproduced with permission from [53]).
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Figure 2: Normal neuronal migration in the mammalian cortex. A. Snapshots of the neuronal migration simulation. Radial progenitor glial cells (pink) proliferate asymmetrically giving rise to neuroblasts (red). Neuroblasts migrate radially on the glial fiber. Neuroblasts adopt a multipolar stage (green) and migrate independently from the glial fiber. Multipolar neurons re-associate with the glial fiber, enter the bipolar migration (yellow) and accumulate on the pile surface. B. Histology of the mouse cortex at embryonic day 16 (reproduced with permission from [53]).

Mentions: Model executions provided a dynamic representation of neuronal migration in the cortex (Figure 2A and the movie in Additional File 1). Neuroblasts (red) proliferated from the glial mother cells (pink) and migrated along the glial fiber in the VZ/SVZ radially toward the IZ. On entry to the IZ, neurons adopt the multipolar stage and migrate randomly both horizontally and vertically independent from the glial fiber (green). Finally, neurons adopted a bipolar state (yellow) and re-associated to a glial fiber. The neurons maintained glial-guided radial migration when locating from the IZ to the CP. Having entered the CP, they continued vertical bipolar migration before dissociating from the fiber in response to Reelin and subsequently accumulating in layers at the CP.


How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex.

Setty Y, Chen CC, Secrier M, Skoblov N, Kalamatianos D, Emmott S - BMC Syst Biol (2011)

Normal neuronal migration in the mammalian cortex. A. Snapshots of the neuronal migration simulation. Radial progenitor glial cells (pink) proliferate asymmetrically giving rise to neuroblasts (red). Neuroblasts migrate radially on the glial fiber. Neuroblasts adopt a multipolar stage (green) and migrate independently from the glial fiber. Multipolar neurons re-associate with the glial fiber, enter the bipolar migration (yellow) and accumulate on the pile surface. B. Histology of the mouse cortex at embryonic day 16 (reproduced with permission from [53]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198702&req=5

Figure 2: Normal neuronal migration in the mammalian cortex. A. Snapshots of the neuronal migration simulation. Radial progenitor glial cells (pink) proliferate asymmetrically giving rise to neuroblasts (red). Neuroblasts migrate radially on the glial fiber. Neuroblasts adopt a multipolar stage (green) and migrate independently from the glial fiber. Multipolar neurons re-associate with the glial fiber, enter the bipolar migration (yellow) and accumulate on the pile surface. B. Histology of the mouse cortex at embryonic day 16 (reproduced with permission from [53]).
Mentions: Model executions provided a dynamic representation of neuronal migration in the cortex (Figure 2A and the movie in Additional File 1). Neuroblasts (red) proliferated from the glial mother cells (pink) and migrated along the glial fiber in the VZ/SVZ radially toward the IZ. On entry to the IZ, neurons adopt the multipolar stage and migrate randomly both horizontally and vertically independent from the glial fiber (green). Finally, neurons adopted a bipolar state (yellow) and re-associated to a glial fiber. The neurons maintained glial-guided radial migration when locating from the IZ to the CP. Having entered the CP, they continued vertical bipolar migration before dissociating from the fiber in response to Reelin and subsequently accumulating in layers at the CP.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Science Laboratory, Microsoft Research, Cambridge, CB3 0FB, UK. yaki.setty@gmail.com

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.

Show MeSH
Related in: MedlinePlus