Abstract
Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. Simulations predict redundancies between lower level sibling SCPs within each type of high level SCP. In contrast, higher level SCPs, such as vesicle transport and exocytosis or microtubule growth characteristic of each type need to be strictly coordinated with each other and imbalances result in stalling of neurite outgrowth. From these simulations, we predicted the effect of changing the activities of SCPs involved in vesicle exocytosis or microtubule growth could lead to formation of dystrophic bulbs. siRNA ablation experiments verified these predictions. We conclude that whole cell dynamics requires balance between the higher-level SCPs involved and imbalances can terminate whole cell responses such as neurite outgrowth.
Highlights
Neurite outgrowth is an early event that changes the state of neurons [1] and allows neurons to develop axons and dendritic trees that connect to other neurons and become electrically active
Model description: Integration of subcellular processes involved in vesicle production, transport and exocytosis and microtubule dynamics to model neurite outgrowth
Failure of growth and the subsequent formation of dystrophic bulb (Fig 1A right panel) can be hypothesized as failure of subcellular processes (SCPs) to function “properly” with respect to each other. To understand how this lack of coordination between SCPs occurs it is necessary to have a detailed description of the SCPs and their relationships as part of setting up the computational model we provide a detailed description of SCPs and their relationships
Summary
Neurite outgrowth is an early event that changes the state of neurons [1] and allows neurons to develop axons and dendritic trees that connect to other neurons and become electrically active. When there is nerve injury and the axons are severed, the process of regeneration which is similar to neurite outgrowth often fails, resulting in the formation of bulbs at the ends of regenerating axons. These bulbs are called dystrophic bulbs [2]. Some of the cellular pathways involved in axonal regeneration, failure and formation of the dystrophic bulbs are known [3, 4] the mechanisms by which these lead to failure are not well understood. In this study we have used an integrated computational and experimental approach to understand the origins of dystrophic bulbs and more generally the conditions under which whole cell responses such as neurite outgrowth can be maintained. The central question we asked in this study is whether quantitative imbalances between subcellular processes can lead to the formation of dystrophic bulbs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
