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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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Illustration of the neuronal migration process and the simplified set of rules in the in-silico model. A: An illustration of neuronal migration (reproduced with permission from [1]). Radial progenitor glial cells (RP; designated by a pink cell with a fiber) proliferate to give rise to neuroblasts (PN; designated by a red cell). Neuroblasts migrate guided by the glial fiber at the ventricular zone and subventricular zone (VZ/SVZ). Neuroblasts adopt the multipolar stage (MS; designated by a green star-like cell) when entering the intermediate zone (IZ) and migrate independently from the glial fiber (on both X and Y directions). In the cortical plate (CP) neurons adopt bipolar state (designated in yellow), associate with the glial fiber and accumulate on top of the pile. The histology images correspond to the various migration stages of the migrating neurons: neuroblasts (bottom-left), multipolar stage neurons (right) and bipolar neurons (top-left). B: Description of the interaction scheme in the model: GABAA detects low concentrations of GABA neurotransmitter in the cortex, but maintains its activity for short periods. GABAA in its active form promotes the activity of Lis1. GABAB requires higher concentrations of the neurotransmitter. Active GABAB promotes both Lis1 and DCX independently. Active Lis1 and active DCX promote Astrotactin adhesion with the glial fiber. The two Reelin Receptors (VLDLR and ApoER2) act as one unit that detects Reelin to reduce the ability of Astrotactin to adhere with the glial fiber one activated.
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Figure 1: Illustration of the neuronal migration process and the simplified set of rules in the in-silico model. A: An illustration of neuronal migration (reproduced with permission from [1]). Radial progenitor glial cells (RP; designated by a pink cell with a fiber) proliferate to give rise to neuroblasts (PN; designated by a red cell). Neuroblasts migrate guided by the glial fiber at the ventricular zone and subventricular zone (VZ/SVZ). Neuroblasts adopt the multipolar stage (MS; designated by a green star-like cell) when entering the intermediate zone (IZ) and migrate independently from the glial fiber (on both X and Y directions). In the cortical plate (CP) neurons adopt bipolar state (designated in yellow), associate with the glial fiber and accumulate on top of the pile. The histology images correspond to the various migration stages of the migrating neurons: neuroblasts (bottom-left), multipolar stage neurons (right) and bipolar neurons (top-left). B: Description of the interaction scheme in the model: GABAA detects low concentrations of GABA neurotransmitter in the cortex, but maintains its activity for short periods. GABAA in its active form promotes the activity of Lis1. GABAB requires higher concentrations of the neurotransmitter. Active GABAB promotes both Lis1 and DCX independently. Active Lis1 and active DCX promote Astrotactin adhesion with the glial fiber. The two Reelin Receptors (VLDLR and ApoER2) act as one unit that detects Reelin to reduce the ability of Astrotactin to adhere with the glial fiber one activated.

Mentions: To construct a model that reproduces the distinct stages of the migration process (as illustrated in Figure 1A), we specified the interaction scheme shown in Figure 1B (see Methods for details of model formulation, construction and simulation). The model makes a number of simplifying assumptions: First, interactions occur between five extracellular mediators (GABAA, GABAB, ApoER2, VLDLR and Astrotactin) that regulate two intracellular regulators (Lis1, DCX). A decreasing GABA concentration gradient exists from the CP toward the VZ [1,7] reflected by a trend in Reelin activity over the CP [3,20]. Our second assumption is that once the GABAA receptor of a neuroblast detects GABA, it promotes Lis1 activity to maintain the glial fiber association [21]. This assumption is based on previously published possible relationships between GABA and Lis1 in C. elegans [22], and in-vitro experiments that suggested that GABA induces dissociated neurons to migrate from the VZ to the IZ [2] via GABAA receptor, which possibly plays role in neuron movement [7]. Third, we specify that GABAA activity is reduced to a level below that required to promote Lis1. Consequently, neurons enter the multipolar stage and disassociate from the glial fiber to migrate randomly in both X and Y directions [1,23]. Fourth, when GABAB detects higher concentrations of GABA, it activates Lis1 and DCX to re-associate with the fiber and to enter the bipolar stage. This is based on observations that GABAB receptors promote migration from the IZ to the CP [1,7], and on a suggested role for DCX in stabilizing neurons association with the glial fiber [2]. Finally, bipolar neurons migrate radially until the Reelin receptors (i.e., ApoER2 and VLDLR) detect and bind to Reelin (i.e., the stop signal) and inhibit neuron's adherence ability to the glial fiber. In turn, neurons dissociate from the glial fiber and accumulate on the next layer in the CP [4,20]. To simplify the complex mechanism by which Lis1, DCX and Reelin regulate the association with the fiber, we defined for modeling purposes that these molecular components mediate the adherence ability of neurons to the fiber through interaction with the Astrotactin protein that mediates the neuron-glial adhesion ligand (although no experimental evidence supports this assumption) [19].


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)

Illustration of the neuronal migration process and the simplified set of rules in the in-silico model. A: An illustration of neuronal migration (reproduced with permission from [1]). Radial progenitor glial cells (RP; designated by a pink cell with a fiber) proliferate to give rise to neuroblasts (PN; designated by a red cell). Neuroblasts migrate guided by the glial fiber at the ventricular zone and subventricular zone (VZ/SVZ). Neuroblasts adopt the multipolar stage (MS; designated by a green star-like cell) when entering the intermediate zone (IZ) and migrate independently from the glial fiber (on both X and Y directions). In the cortical plate (CP) neurons adopt bipolar state (designated in yellow), associate with the glial fiber and accumulate on top of the pile. The histology images correspond to the various migration stages of the migrating neurons: neuroblasts (bottom-left), multipolar stage neurons (right) and bipolar neurons (top-left). B: Description of the interaction scheme in the model: GABAA detects low concentrations of GABA neurotransmitter in the cortex, but maintains its activity for short periods. GABAA in its active form promotes the activity of Lis1. GABAB requires higher concentrations of the neurotransmitter. Active GABAB promotes both Lis1 and DCX independently. Active Lis1 and active DCX promote Astrotactin adhesion with the glial fiber. The two Reelin Receptors (VLDLR and ApoER2) act as one unit that detects Reelin to reduce the ability of Astrotactin to adhere with the glial fiber one activated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Illustration of the neuronal migration process and the simplified set of rules in the in-silico model. A: An illustration of neuronal migration (reproduced with permission from [1]). Radial progenitor glial cells (RP; designated by a pink cell with a fiber) proliferate to give rise to neuroblasts (PN; designated by a red cell). Neuroblasts migrate guided by the glial fiber at the ventricular zone and subventricular zone (VZ/SVZ). Neuroblasts adopt the multipolar stage (MS; designated by a green star-like cell) when entering the intermediate zone (IZ) and migrate independently from the glial fiber (on both X and Y directions). In the cortical plate (CP) neurons adopt bipolar state (designated in yellow), associate with the glial fiber and accumulate on top of the pile. The histology images correspond to the various migration stages of the migrating neurons: neuroblasts (bottom-left), multipolar stage neurons (right) and bipolar neurons (top-left). B: Description of the interaction scheme in the model: GABAA detects low concentrations of GABA neurotransmitter in the cortex, but maintains its activity for short periods. GABAA in its active form promotes the activity of Lis1. GABAB requires higher concentrations of the neurotransmitter. Active GABAB promotes both Lis1 and DCX independently. Active Lis1 and active DCX promote Astrotactin adhesion with the glial fiber. The two Reelin Receptors (VLDLR and ApoER2) act as one unit that detects Reelin to reduce the ability of Astrotactin to adhere with the glial fiber one activated.
Mentions: To construct a model that reproduces the distinct stages of the migration process (as illustrated in Figure 1A), we specified the interaction scheme shown in Figure 1B (see Methods for details of model formulation, construction and simulation). The model makes a number of simplifying assumptions: First, interactions occur between five extracellular mediators (GABAA, GABAB, ApoER2, VLDLR and Astrotactin) that regulate two intracellular regulators (Lis1, DCX). A decreasing GABA concentration gradient exists from the CP toward the VZ [1,7] reflected by a trend in Reelin activity over the CP [3,20]. Our second assumption is that once the GABAA receptor of a neuroblast detects GABA, it promotes Lis1 activity to maintain the glial fiber association [21]. This assumption is based on previously published possible relationships between GABA and Lis1 in C. elegans [22], and in-vitro experiments that suggested that GABA induces dissociated neurons to migrate from the VZ to the IZ [2] via GABAA receptor, which possibly plays role in neuron movement [7]. Third, we specify that GABAA activity is reduced to a level below that required to promote Lis1. Consequently, neurons enter the multipolar stage and disassociate from the glial fiber to migrate randomly in both X and Y directions [1,23]. Fourth, when GABAB detects higher concentrations of GABA, it activates Lis1 and DCX to re-associate with the fiber and to enter the bipolar stage. This is based on observations that GABAB receptors promote migration from the IZ to the CP [1,7], and on a suggested role for DCX in stabilizing neurons association with the glial fiber [2]. Finally, bipolar neurons migrate radially until the Reelin receptors (i.e., ApoER2 and VLDLR) detect and bind to Reelin (i.e., the stop signal) and inhibit neuron's adherence ability to the glial fiber. In turn, neurons dissociate from the glial fiber and accumulate on the next layer in the CP [4,20]. To simplify the complex mechanism by which Lis1, DCX and Reelin regulate the association with the fiber, we defined for modeling purposes that these molecular components mediate the adherence ability of neurons to the fiber through interaction with the Astrotactin protein that mediates the neuron-glial adhesion ligand (although no experimental evidence supports this assumption) [19].

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