Computational model of axon guidance

Abstract

Axon guidance (AG) towards their target during embryogenesis or after injury is an important issue in the development of neuronal networks. During their growth, axons often face complex decisions that are difficult to understand when observing just a small part of the problem. In this work we propose a computational model of AG based on activity-independent mechanisms that takes into account the most important aspects of AG. The model includes the main elements (neurons, with soma, axon and growth cone; glial cells acting as guideposts) and mechanisms (attraction/repulsion guidance cues, growth cone adaptation, tissue-gradient intersections, axonal transport, changes in the growth cone complexity and a range of responses for each receptor). The growth cone guidance is defined as a function that maps the receptor activation by ligands into a repulsive or attractive force. This force is then converted into a turn- ing angle using spherical coordinates. A regulatory network between the receptors and the intracellular proteins is considered, leading to more complex and realistic behaviors. The ligand diffusion through the extracellular environment is modeled with linear or exponential functions. Concerning experimentation, it was developed the first computational model and a new theoretical model of the midline crossing of Drosophila axons that focus all the decision points. The computational model created allows describing to a great extent the behaviors that have been reported in the literature, for three different pathfinding scenarios: (i) normal, (ii) comm mutant and (iii) robo mutant. Moreover, this model suggests new hypotheses, being the most relevant the existence of an inhibitory link between the DCC receptor and the Comm protein that is Netrin-mediated or mediated by a third unknown signal.