Distinct cellular and molecular mechanisms mediate initial axon development and adult-stage axon regeneration in C. elegans

Department of Physics and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
Development (Impact Factor: 6.27). 04/2008; 135(6):1129-36. DOI: 10.1242/dev.013995
Source: PubMed

ABSTRACT The molecular and cellular mechanisms that allow adult-stage neurons to regenerate following damage are poorly understood. Recently, axons of motoneurons and mechanosensory neurons in adult C. elegans were found to regrow after being snipped by femtosecond laser ablation. Here, we explore the molecular determinants of adult-stage axon regeneration using the AVM mechanosensory neurons. The first step in AVM axon development is a pioneer axonal projection from the cell body to the ventral nerve cord. We show that regeneration of the AVM axon to the ventral nerve cord lacks the deterministic precision of initial axon development, requiring competition and pruning of unwanted axon branches. Nevertheless, axons of injured AVM neurons regrow to the ventral nerve cord with over 60% reliability in adult animals. In addition, in contrast to initial development, axon guidance during regeneration becomes heavily dependent on cytoplasmic protein MIG-10/Lamellipodin but independent of UNC-129/TGF-beta repellent and UNC-40/DCC receptor, and axon growth during regeneration becomes heavily dependent on UNC-34/Ena and CED-10/Rac actin regulators. Thus, C. elegans may be used as a genetic system to characterize novel cellular and molecular mechanisms underlying adult-stage nervous system regeneration.

Download full-text


Available from: Christopher Gabel, Jun 19, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Regeneration capabilities are found in most or all animals. Whether regeneration is part of the development of an animal or a distinct phenomenon independent of development is a debatable question. If we consider regeneration as a process belonging to development, similarly to embryogenesis or metamorphosis, the existence of regenerative capabilities in adults can be seen as an argument in favor of the theory that development continues throughout the life of animals. Here I perform a comparative analysis of regeneration versus “classical” developmental processes in animals in order to determine to what extent these processes are inclusive or distinct. I identify the existence of regeneration-specific processes, i.e., processes that occur during the regeneration, but not the initial development, of a given structure. In addition, I find that seemingly similar processes acting during development and regeneration may have differential molecular and cellular bases. I thus conclude that there are significant differences between regeneration processes in adult animals and developmental processes occurring during earlier phases of the life cycle. The existence of regenerative capabilities in adult animals can therefore not be used as an argument in favor of the idea that development spans the whole life. KeywordsCell differentiation–Dedifferentiation–Development–Epimorphosis–Molecular mechanisms–Regeneration–Stem cells
    Biological Theory 12/2011; 6(1):25-35. DOI:10.1007/s13752-011-0005-3
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A C. elegans mechanosensory neuron expressing GFP undergoes regenerative growth following laserinduced injury. A growth cone, sprouting from the proximal side of the axon, extends towards the separated distal fragment in an attempt to reconnect and fuse. The fluorescent image was digitally duplicated twice and re-colored (Graphic designer: Dee McGrath). From Neumann et al., Developmental Dynamics 240:1365-1372, 2011.
    Developmental Dynamics 07/2011; 240(7):spcone. DOI:10.1002/dvdy.22682 · 2.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Functional neuronal recovery following injury arises when severed axons reconnect with their targets. In Caenorhabditis elegans following laser-induced axotomy, the axon still attached to the cell body is able to regrow and reconnect with its separated distal fragment. Here we show that reconnection of separated axon fragments during regeneration of C. elegans mechanosensory neurons occurs through a mechanism of axonal fusion, which prevents Wallerian degeneration of the distal fragment. Through electron microscopy analysis and imaging with the photoconvertible fluorescent protein Kaede, we show that the fusion process re-establishes membrane continuity and repristinates anterograde and retrograde cytoplasmic diffusion. We also provide evidence that axonal fusion occurs with a remarkable level of accuracy, with the proximal re-growing axon recognizing its own separated distal fragment. Thus, efficient axonal regeneration can occur by selective reconnection and fusion of separated axonal fragments beyond an injury site, with restoration of the damaged neuronal tract.
    Developmental Dynamics 06/2011; 240(6):1365-72. DOI:10.1002/dvdy.22606 · 2.67 Impact Factor