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Although synaptic evolution has been extensively studied, how axons first arose remains unexplored. Because evolution often occurs by coopting existing features, we review the evolutionary histories, biophysics, and cell biology of cytokinesis, cell crawling, and ciliogenesis to explore the origin of axons. Although we found that cilia and axons are outwardly similar, and growth cones strongly resemble the leading edge of crawling cells, the biophysical processes and the critical proteins that drive each seem weakly linked to axons as a structure. In contrast, the traction force machinery that pulls daughter cells apart during cytokinesis and the cytoskeletal organization of cytokinetic bridges appear to have a one-to-one correspondence to neuronal growth cones and axons. Based on these observations, we propose the hypothesis that axons evolved due to mutations that partially activated cytokinesis in an interphase cell. To rigorously test this hypothesis, we suggest conducting systematic phylogenetic analysis of the genes essential for each process, paired with molecular genetic studies in which critical genes are systematically disrupted. Doing so will provide a framework for understanding the relationship between diverse cellular processes, the early evolution of neurons, and insights that could potentially assist in treating cancer and promoting neuronal regeneration. 

While the structural organization and molecular biology of neurons are well characterized, the physical process of axonal elongation remains elusive. The classic view posited elongation occurs through the deposition of cytoskeletal elements in the growth cone at the tip of a stationary array of microtubules. Yet, recent studies reveal axonal microtubules and docked organelles flow forward in bulk in the elongating axons ofAplysia, chick sensory, rat hippocampal, andDrosophilaneurons. Noting that the morphology, molecular components, and subcellular flow patterns of growth cones strongly resemble the leading edge of migrating cells and the polar regions of dividing cells, our working hypothesis is that axonal elongation utilizes the same physical mechanisms that drive cell crawling and cell division. As a test of that hypothesis, here we take experimental data sets of sub-cellular flow patterns in cells undergoing cytokinesis, mesenchymal migration, amoeboid migration, neuronal migration, and axonal elongation. We then apply active fluid theory to develop a biophysical model that describes the different sub-cellular flow profiles across these forms of motility and how this generates cell motility under low Reynolds numbers. The modeling suggests that mechanisms for generating motion are shared across these processes, and differences arise through modifications of sub-cellular adhesion patterns and the profiles of internal force generation. Collectively, this work suggests that ameboid and mesenchymal cell crawling may have arisen from processes that first developed to support cell division, that growth cone motility and cell crawling are closely related, and that neuronal migration and axonal elongation are fundamentally similar, differing primarily in the motion and strength of adhesion under the cell body.