A hybrid computational model to predict chemotactic guidance of growth cones

Iolanda Morana Roccasalvo, Silvestro Micera, Pier Nicola Sergi
2015 Scientific Reports  
The overall strategy used by growing axons to find their correct paths during the nervous system development is not yet completely understood. Indeed, some emergent and counterintuitive phenomena were recently described during axon pathfinding in presence of chemical gradients. Here, a novel computational model is presented together with its ability to reproduce both regular and counterintuitive axonal behaviours. In this model, the key role of intracellular calcium was phenomenologically
more » ... ed through a non standard Gierer-Meinhardt system, as a crucial factor influencing the growth cone behaviour both in regular and complex conditions. This model was able to explicitly reproduce neuritic paths accounting for the complex interplay between extracellular and intracellular environments, through the sensing capability of the growth cone. The reliability of this approach was proven by using quantitative metrics, numerically supporting the similarity between in silico and biological results in regular conditions (control and attraction). Finally, the model was able to qualitatively predict emergent and counterintuitive phenomena resulting from complex boundary conditions. Axons establish highly specific connections to wire and develop the nervous system 1 . Pathfinding axons navigate through the body towards specific targets by sensing environmental characteristics 2 and by following diffusible gradients of chemical cues 3-6 . This result is achieved by an extremely sensitive detector of chemical gradient: the growth cone 7 (GC). The GC can sense diffusible gradients and move toward secretive targets 8-12 through a chemotactic guidance process, which involves the amplification of external chemical signals through an internal transduction process 11,13 . From a biological point of view, it is well known 14 that calcium (Ca 2+ ) is a key regulator of several important phenomena deeply involved in axonal guidance, as the promotion and inhibition of axonal outgrowth and growth cone turning 15 . Experimental correlations were found between directional increase of intracellular calcium concentration ([Ca 2+ ] i ) and biased protrusion of filopodia 16-19 resulting in oriented outgrowth of axons 16, 20, 21 . An increased level of [Ca 2+ ] i was found to be spread across the growth cone domain as well as clustered in micro-domains. These wide differences in gradient shape and magnitude were due to the complex interplay between Ca 2+ homeostatic mechanisms and calcium influxes from membrane channels and calcium release from internal calcium stores 14 . In addition, more complex, and unexpected axonal behaviours were described when extracellular calcium concentration ([Ca 2+ ] e ) changed, so the attractive/repulsive nature of guidance cues was related to both [Ca 2+ ] i and [Ca 2+ ] e 21 . As a consequence, since intracellular and extracellular [Ca 2+ ] influence each other, the GC membrane likely plays an important role in axonal steering, particularly through the dynamics of surface receptors 22 .
doi:10.1038/srep11340 pmid:26086936 pmcid:PMC4471899 fatcat:uuiyurlvo5brbdaz7z23aznblm