Can Molecular Motors Drive Distance Measurements in Injured Neurons?

Injury to nerve axons induces diverse responses in neuronal cell bodies, some of which are influenced by the distance from the site of injury. This suggests that neurons have the capacity to estimate the distance of the injury site from their cell body. Recent work has shown that the molecular motor dynein transports importin-mediated retrograde signaling complexes from axonal lesion sites to cell bodies, raising the question whether dynein-based mechanisms enable axonal distance estimations in injured neurons? We used computer simulations to examine mechanisms that may provide nerve cells with dynein-dependent distance assessment capabilities. A multiple-signals model was postulated based on the time delay between the arrival of two or more signals produced at the site of injury–a rapid signal carried by action potentials or similar mechanisms and slower signals carried by dynein. The time delay between the arrivals of these two types of signals should reflect the distance traversed, and simulations of this model show that it can indeed provide a basis for distance measurements in the context of nerve injuries. The analyses indicate that the suggested mechanism can allow nerve cells to discriminate between distances differing by 10% or more of their total axon length, and suggest that dynein-based retrograde signaling in neurons can be utilized for this purpose over different scales of nerves and organisms. Moreover, such a mechanism might also function in synapse to nucleus signaling in uninjured neurons. This could potentially allow a neuron to dynamically sense the relative lengths of its processes on an ongoing basis, enabling appropriate metabolic output from cell body to processes

A Motor-Driven Mechanism for Cell-Length Sensing

Size homeostasis is fundamental in cell biology, but it is not clear how large cells such as neurons can assess their own size or length. We examined a role for molecular motors in intracellular length sensing. Computational simulations suggest that spatial information can be encoded by the frequency of an oscillating retrograde signal arising from a composite negative feedback loop between bidirectional motor-dependent signals. The model predicts that decreasing either or both anterograde or retrograde signals should increase cell length, and this prediction was confirmed upon application of siRNAs for specific kinesin and/or dynein heavy chains in adult sensory neurons. Heterozygous dynein heavy chain 1 mutant sensory neurons also exhibited increased lengths both in vitro and during embryonic development. Moreover, similar length increases were observed in mouse embryonic fibroblasts upon partial downregulation of dynein heavy chain 1. Thus, molecular motors critically influence cell-length sensing and growth control

A grand challenge for computing: Towards full reactive modeling of a multi-cellular animal

challenge is really a direct outcome of our interaction, and many of the points made herein are outcomes of discussions with them. In particular, Naaman Kam deserves special thanks for initiating the group’s joint work on C. elegans, and thus causing that particular organism to be the focus of the challenge proposed here. Biological systems can be modeled beneficially as reactive systems, using languages and tools developed for the construction of man-made systems. Our long-term aim is to model a full multicellular animal as a reactive system---- specifically, the C. elegans nematode worm, which is complex, but very well-defined in terms of anatomy and genetics. The challenge is to construct a full, true-to-all-known-facts, 4-dimensional, fully animated model of the development and behavior of this worm (or of a comparable multi-cellular animal), which is easily extendable as new biological facts are discovered. 1