Multi-phasic bi-directional chemotactic responses of the growth cone

Abstract

The nerve growth cone is bi-directionally attracted and repelled by the same cue molecules depending on the situations, while other non-neural chemotactic cells usually show uni-directional attraction or repulsion toward their specific cue molecules. However, how the growth cone differs from other non-neural cells remains unclear. Toward this question, we developed a theory for describing chemotactic response based on a mathematical model of intracellular signaling of activator and inhibitor. Our theory was first able to clarify the conditions of attraction and repulsion, which are determined by balance between activator and inhibitor, and the conditions of uni- and bi-directional responses, which are determined by dose-response profiles of activator and inhibitor to the guidance cue. With biologically realistic sigmoidal dose-responses, our model predicted tri-phasic turning response depending on intracellular Ca2+ level, which was then experimentally confirmed by growth cone turning assays and Ca2+ imaging. Furthermore, we took a reverse-engineering analysis to identify balanced regulation between CaMKII (activator) and PP1 (inhibitor) and then the model performance was validated by reproducing turning assays with inhibitions of CaMKII and PP1. Thus, our study implies that the balance between activator and inhibitor underlies the multi-phasic bi-directional turning response of the growth cone.

Revisiting Chemoaffinity Theory:Chemotactic Implementation of Topographic Axonal Projection

“…I examined how chemotactic responses vary with absolute concentrations in the gradient. My previous study [27] showed that the steady-state response of ∆ / * was presented by…”

“…Chemotactic gradient sensing has been computationally studied mainly for non-neural chemotactic cells [40,[47][48][49][50][51] like Dictyostelium discoideum and immune cells, though attraction to guidance cues has been only paid attention. On the other hand, there are a couple of computational models for the growth cone chemotaxis alternating attraction and repulsion [27,52]. These models, whether applied to neural or nonneural cells, primarily addressed intracellular signaling consisting of activators and inhibitors.…”

“…In the nonneural cells, the activator and inhibitor were thought to be PI3K and PTEN [28], respectively, or RasGEF and RasGAP [29], respectively. In the growth cone, CaMKII and PP1 were thought to work as the activator and inhibitor, respectively [27,30,31,52], which regulate cellular motility via Rho GTPases [53]. In short, chemotactic responses could be understood from the activator-inhibitor framework [54], so I hypothesized that RGC chemotaxis is also regulated by an activator-inhibitor system, although the intracellular signaling pathway of Eph/ephrin has not been fully identified.…”

“…Chemotactic gradient sensing has been computationally studied mainly for non-neural chemotactic cells [35-5 39] like Dictyostelium discoideum and immune cells, though several studies have examined the growth cone [23,40]. These models, whether applied to neural or non-neural cells, primarily addressed intracellular signaling consisting of activators and inhibitors.…”

Self-organization mechanism of distinct microtubule orientations in axons and dendrites

“…1A). The growing neurite (major neurite) becomes an axon, which subsequently migrates to connect with the target neurons [2], whereas the remaining neurites (minor neurites) grow slowly, thereby developing into dendrites. However, how the major and minor neurites, which differ only in length and growth speed, acquire the different identities of the axon and the dendrites remains elusive.…”