An official website of the United States government
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.
more »
« less
This content will become publicly available on September 1, 2026
Did axons evolve by activating cytokinesis during interphase? A hypothesis on the origin of neurons
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.
more »
« less
- Award ID(s):
- 1915477
- PAR ID:
- 10656084
- Editor(s):
- Onishi, Masayuki
- Publisher / Repository:
- Molecular Biology of the Cell
- Date Published:
- Journal Name:
- Molecular Biology of the Cell
- Volume:
- 36
- Issue:
- 9
- ISSN:
- 1059-1524
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Mogilner, Alex (Ed.)The cross-sectional area of myelinated axons increases greatly during postnatal development in mammals and is an important influence on axonal conduction velocity. This radial growth is driven primarily by an accumulation of neurofilaments, which are cytoskeletal polymers that serve a space-filling function in axons. Neurofilaments are assembled in the neuronal cell body and transported into axons along microtubule tracks. The maturation of myelinated axons is accompanied by an increase in neurofilament gene expression and a decrease in neurofilament transport velocity, but the relative contributions of these processes to the radial growth are not known. Here, we address this question by computational modeling of the radial growth of myelinated motor axons during postnatal development in rats. We show that a single model can explain the radial growth of these axons in a manner consistent with published data on axon caliber, neurofilament and microtubule densities, and neurofilament transport kinetics in vivo. We find that the increase in the cross-sectional area of these axons is driven primarily by an increase in the influx of neurofilaments at early times and by a slowing of neurofilament transport at later times. We show that the slowing can be explained by a decline in the microtubule density.more » « less
-
Dague, Etienne (Ed.)The formation of neuron networks is a complex phenomenon of fundamental importance for understanding the development of the nervous system, and for creating novel bioinspired materials for tissue engineering and neuronal repair. The basic process underlying the network formation is axonal growth, a process involving the extension of axons from the cell body towards target neurons. Axonal growth is guided by environmental stimuli that include intercellular interactions, biochemical cues, and the mechanical and geometrical features of the growth substrate. The dynamics of the growing axon and its biomechanical interactions with the growing substrate remains poorly understood. In this paper, we develop a model of axonal motility which incorporates mechanical interactions between the axon and the growth substrate. We combine experimental data with theoretical analysis to measure the parameters that describe axonal growth on surfaces with micropatterned periodic geometrical features: diffusion (cell motility) coefficients, speed and angular distributions, and axon bending rigidities. Experiments performed on neurons treated Taxol (inhibitor of microtubule dynamics) and Blebbistatin (disruptor of actin filaments) show that the dynamics of the cytoskeleton plays a critical role in the axon steering mechanism. Our results demonstrate that axons follow geometrical patterns through a contact-guidance mechanism, in which high-curvature geometrical features impart high traction forces to the growth cone. These results have important implications for our fundamental understanding of axonal growth as well as for bioengineering novel substrates that promote neuronal growth and nerve repair.more » « less
-
Abstract Possessing only essential genes, a minimal cell can reveal mechanisms and processes that are critical for the persistence and stability of life1,2. Here we report on how an engineered minimal cell3,4contends with the forces of evolution compared with theMycoplasma mycoidesnon-minimal cell from which it was synthetically derived. Mutation rates were the highest among all reported bacteria, but were not affected by genome minimization. Genome streamlining was costly, leading to a decrease in fitness of greater than 50%, but this deficit was regained during 2,000 generations of evolution. Despite selection acting on distinct genetic targets, increases in the maximum growth rate of the synthetic cells were comparable. Moreover, when performance was assessed by relative fitness, the minimal cell evolved 39% faster than the non-minimal cell. The only apparent constraint involved the evolution of cell size. The size of the non-minimal cell increased by 80%, whereas the minimal cell remained the same. This pattern reflected epistatic effects of mutations inftsZ, which encodes a tubulin-homologue protein that regulates cell division and morphology5,6. Our findings demonstrate that natural selection can rapidly increase the fitness of one of the simplest autonomously growing organisms. Understanding how species with small genomes overcome evolutionary challenges provides critical insights into the persistence of host-associated endosymbionts, the stability of streamlined chassis for biotechnology and the targeted refinement of synthetically engineered cells2,7–9.more » « less
-
RNA regulation plays a critical role in mitosis, yet the mechanisms remain unclear. Our lab recently identified that the conserved RNA-Binding Protein (RBP), ATX-2, regulates cytokinesis by regulating the targeting of ZEN-4 to the spindle midzone through a conserved translation regulator, PAR-5/14-3-3sigma (Gnazzo et al., 2016). While co-depletion of ATX-2 and PAR-5 restored ZEN-4 targeting to the spindle midzone, it did not rescue cell division. To identify factors that may work in concert with ATX-2 to regulate cell division, we conducted a two-part, candidate RNAi suppressor and visual screen to identify factors that are important for cell division and also mediate the targeting of ATX-2 to the centrosomes and the spindle midzone. Using this approach, we identified ten genes that suppress the embryonic lethality defect observed in atx-2 mutant embryos. These ten genes, including act-2, cgh-1, cki-1, hum-6, par-2, rnp-4, vab-3, vhl-1, vps-24, and wve-1, all have some role regulating RNA or the cell cycle. Five of these genes (cgh-1, cki-1, vab-3, vhl-1, vps-24) fail to target ATX-2 to the centrosomes and midzone when depleted. The strongest suppressor of the atx-2 phenotype is the DEAD-box RNA helicase CGH-1/DDX6, which has been implicated in cell division, RNA processing and translation, and neuronal function. Loss of CGH-1 rescued the cytokinesis defect and also restored ZEN-4 localization to the spindle midzone. ATX-2 and CGH-1 are mutually required for their localization to centrosomes and the spindle midzone. Our findings provide the first functional evidence that CGH-1/DDX6 regulates ATX-2 function during mitosis to target ZEN-4 to the spindle midzone via PAR-5/14-3-3sigma. We suggest that RNA machinery is necessary for the completion of cytokinesis.more » « less
