Neuronal self-avoidance, or isoneural avoidance, is an important property of neurons which consists in the tendency of branches (dendrites and axons) arising from a single soma (also called isoneuronal or sister branches) to turn away from one another. The arrangements of branches within neuronal arbors are established during development and result in minimal crossing or overlapKramer AP, Stent GS. 1985. Developmental arborization of sensory neurons in the leech Haementeria ghilianii. II. Experimentally induced variations in the branching pattern. J. Neurosci., 5:768–75 as they spread over a territory, resulting in the typical fasciculated morphology of neurons (Fig 1).
In opposition, branches from different neurons can overlap freely with one another. This propriety demands that neurons are able to discriminate "self", which they avoid, from "non-self" branches, with which they coexist.Kramer AP, Kuwada JY. 1983. Formation of the receptive fields of leech mechanosensory neurons during embryonic development. J. Neurosci. 3:2474–86 This neuronal self-recognition is attained through families of cell recognition molecules which work as individual barcodes, allowing the discrimination of any other nearby branch as either "self" or "non-self".Hughes ME, Bortnick R, Tsubouchi A, Baumer P, Kondo M, et al. 2007. Homophilic Dscam interactions control complex dendrite morphogenesis. Neuron. 54:417–27Matthews BJ, KimME, Flanagan JJ, Hattori D, Clemens JC, et al. 2007. Dendrite self-avoidance is controlled by Dscam. Cell 129:593–604Schreiner D, Weiner JA. 2010. Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion. Proc. Natl. Acad. Sci. USA 107:14893–98Lefebvre JL, Kostadinov D, Chen WV, Maniatis T, Sanes JR. 2012. Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature. Wu W, Ahlsen G, Baker D, Shapiro L, Zipursky SL. 2012. Complementary chimeric isoforms reveal Dscam1 binding specificity in vivo. Neuron 74:261–68
Self-avoidance ensures that dendritic territories are covered completely and yet non-redundantlyHoang P, Grueber WB. 2013. Dendritic self-avoidance: protocadherins have it covered. Cell Res. 23:323-325 guaranteeing that branches achieve functionally appropriate coverage of input or output territories.
Neuronal communication requires the coordinated assembly of axons, dendrites, and synapses.Choe Y, Yang HF, Chern-Yeow D. 2007. Autonomous learning of the semantics of internal sensory states based on motor exploration. International Journal of Humanoid Robotics 4:211-243 Therefore, self-avoidance is necessary for proper neuronal wiring and postnatal development and, together with neuronal tiling (heteroneuronal avoidance), is a crucial spacing mechanism for patterning neural circuits that results in complete and nonredundant innervation of sensory or synaptic space.Zipursky, S.L., Grueber W.B. 2013 The molecular basis of self-avoidance. Annu Rev Neurosci. 26:547-568
History
The concept of neuronal self-avoidance emerged about 50 years ago. The pioneer studies were performed in the leech, focusing on the central nervous system and developing mechanosensory neurons. Leeches from two species: Hirudo medicinalis and Haementeria ghilianii, remained the main organism for the study of the question of neuronal self-recognition and self-avoidance. In this animal, the repeating segmental pattern of the nervous system along with the fact that neurons are relatively few in number, and many are large enough to be recognizedNicholls JG, Baylor DA. 1968. Specific modalities and receptive fields of sensory neurons in CNS of the leech. J. Neurophysiol. 31:740–56 allowed the experimental study of the general problem of neuronal specificity. In 1968, through the mapping of mechanoreceptor axonal receptive fields in H. medicilalis, Nicholls and Baylor revealed distinct types of boundaries between axons from the same or different types of neurons, and also between individual neurons. They observed that receptive fields were subdivided into discrete areas, innervated by the different branches of a single cell. These boundaries, unlike those between adjacent fields of different cells, were abrupt showing nearly no overlap. The authors then suggested a mechanism for the spatial arrangement of axons in which "a fiber might repel other branches more strongly if they arise from the same cell than if they come from a homologue, and not at all if they come from a cell with a different modality". In 1976, YauYau KW. 1976. Receptive fields, geometry and conduction block of sensory neurons in the central nervous system of the leech. J. Physiol. 263:513–38 confirmed their findings and proposed that the branches of a cell recognized each other, therefore avoiding to grow into the same territory and establishing the discrete areas that Nicholls and Baylor observed. It was then clear that mechanosensory neurons, in leech, show self-avoidance: with the repulsion between branches originating from the same cell, but they did not show class-avoidance, meaning that branches from the same type of neurons could overlap.
The phenomena was recognized but a lot remained unknown, including the term "Self-avoidance" which arises in 1982/1983 with the studies of Kramer. In 1982, KramerKramer, AP. 1982. The development of neuronal arborizations in the leech. Neuronal Development: Cellular Approaches in Invertebrates. 882-885 postulated that isoneuronal axons (axons growing from the same neuron), contrarily to heteroneuronal axons, avoid each other when growing on the same substrate (see Movie). This was further explored, by other authors, the fact that this self-avoidance would require neurites to be able to distinguish between self and non-self, reinforcing the ideas of Yau. In 1983 Kramer and Kuwada propose that this self-recognition of two growing axonal processes might be mediated by their filopodia, which appear to make mutual contacts. This idea was backed up by the studies of Goodman et al. (1982)Goodman CS, Raper JA, Ho RK, Chang S. 1982. Path-finding of neuronal growth cones in grasshopper embryos. Developmental Order: Its Origin and Regulation. 275-316 in insect neurons, which postulated that filopodia played an important role in the recognition and choice of axonal growth pathways. The conservation of the mechanism in invertebrates together with the fact that adult morphology of many neurons appears to satisfy the rule, suggested that non-overlap of isoneuronal processes could be a general phenomenon of neuronal development. In 1985 empirical data was added by Kramer and Stent with the experimentally induced variations in the branching pattern through surgically preventing or delaying the outgrowth of the axon branches. As predicted by the proposal of self-avoidance, interference with the outgrowth of a field axon branch resulted in the spread of the axon branch of the other field into what normally was not a territory. Thus, neuronal self-avoidance does play a significant role in the development of mechanosensory receptive field structure.
In the late 1980s, the molecular machinery that could be the basis of the phenomena started to be unveiled. Receptors such as cell adhesion molecules of the cadherin and immunoglobulin super families, which mediate interactions between opposing cell surfaces, and integrins acting as receptors for extracellular matrix components were widely expressed on developing neurites.Neugebauer KM, Tomaselli KJ, Lilien J, Reichardt LF. 1988. N-cadherin, NCAM, and integrins promote retinal neurite outgrowth on astrocytes in vitro. J. Cell Biol. 107:1177–87Tomaselli KJ, NeugebauerKM, Bixby JL, Lilien J, Reichardt LF. 1988. N-cadherin and integrins: two receptor systems that mediate neuronal process outgrowth on astrocyte surfaces. Neuron 1:33–43
In 1990, Macagno et al.,Macagno ER, Gao WO, Baptista CA, Passani MB. 1990. Competition or inhibition? Developmental strategies in the establishment of peripheral projections by leech neurons. J. Neurobiol. 21: 107-119 integrated the results from several studies, once again emphasizing the evolutionary conservation of the overall phenomena: Leech neurons, like those of other invertebrates and those of vertebrates, undergo specific interactions during development which allow the definition of the adult morphologies and synaptic connections. That morphology reflects the developmental compromise between the potential of the neuron to grow and the constraints placed upon that growth by internal and external factors. Thus, the self-recognizing mechanism would be useful not only to self-avoidance but also as a means of individualization. During development, competition among neurons of the same type for a limited supply required for process growth and maintenance would occur, with one cell gaining space at the expense of others. Inhibitory interactions were also invoked, and this placed the phenomena of self-recognition in the bigger picture of the axon guidance process. Together, these studies led to the view that neural circuit assembly emerged as a result of a relatively small number of different signals and their receptors, some acting in a graded fashion and in different combinations.Tessier-Lavigne M, Goodman CS. 1996. The molecular biology of axon guidance. Science 274:1123–3
In 1991, scientists became aware that self-avoidance was also present in non-neuronal cell types, such as leech comb cells, which might similarly form discrete domains.Jellies J, Kristan WB. 1991. The oblique muscle organizer in Hirudo medicinalis, an identified cell projecting multiple parallel growth cones in an orderly array. Devi Biol. 148: 334-354 Later, this was also observed in mammalian astrocytes.Bushong EA, Martone ME, Jones YZ, Ellisman MH. 2002. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22(1):183–92Ogata K, Kosaka T. 2002. Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113(1):221–33Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, et al. 2007. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450: 56–62 Wang and Macagno,Wang H, Macagno ER. 1998. A detached branch stops being recognized as self by other branches of a neuron. J. Neurobiol. 35: 53-64 in 1998, again recurring to Hirudo medicinalis mechanosensory neurons, performed an elegant experiment in order to try to answer the still remaining question: "How does a cell recognize self and respond by not growing over or along itself?" The authors then proposed two general types of mechanisms: I) External signals: Sibling neurites display surface identifying molecular factors, unique to each cell, that are capable of homotypic binding and therefore repel sibling neurites, or II) Internal signals: synchronous cell activity, such as voltage, which is transmitted within the cell mediating a dynamic mechanism of sibling growth inhibition. Contrarily to the first hypothesis, the second would require the continuity and communication between all parts of the cell for self-avoidance to occur. So the experiment consisted of detaching one of the neurons dendrites and see how the remaining attached dendrites reacted towards the detached fragment, "do they still avoid overlapping?" The result was that the detached branch would stop being recognized as "self" by the other branches of the neuronal, leading to dendrite overlap. The clear conclusion of the study was that continuity between all parts of the neuron is critical for self-avoidance to operate. The authors then suggest various mechanisms that require continuity and could function as recognition signal, and thus might be the responsible ones, such as "electrical activity, active or passive, as well as the diffusion of cytoplasmic signals either passively or by fast axonal transport".