Multi-phasic bi-directional chemotactic responses of the growth cone.
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.
Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan.|Imaging Platform for Spatio-temporal Information, Kyoto University, Sakyo, Kyoto, Japan.
Honda
H
Naoki
Department of Biochemistry, New York University School of Medicine, New York, USA.|Kasah Technology Inc. New York, New York, USA.
Makoto
M
Nishiyama
Department of Biochemistry, New York University School of Medicine, New York, USA.
Kazunobu
K
Togashi
Olympus Software Technology Corporation, Hachioji, Tokyo, Japan.
Yasunobu
Y
Igarashi
Department of Biochemistry, New York University School of Medicine, New York, USA.|Kasah Technology Inc. New York, New York, USA.
Kyonsoo
K
Hong
Imaging Platform for Spatio-temporal Information, Kyoto University, Sakyo, Kyoto, Japan.|Graduate School of Informatics, Kyoto University, Sakyo, Kyoto, Japan.
Shin
S
Ishii
D000465:Algorithms; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D020439:Growth Cones / Q000502:physiology*; D042541:Intracellular Space / Q000378:metabolism; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D014981:Xenopus
D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054645:Protein Phosphatase 1; D006152:Cyclic GMP; D002118:Calcium