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Mechanisms of Neurite Pruning

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Mechanisms of Neurite Pruning Neuroforum 2017; 23(1): A19–A25 Sebastian Rumpf*, Sandra Rode, Rafael Krumkamp and Svende Herzmann Mechanisms of Neurite Pruning DOI 10.1515/nf-2016-A105 “pruning” (from a gardening expression that means “to weed out branches”) (Schuldiner and Yaron, 2015). For Abstract: The axons, dendrites and synapses of neurons example, after a phase of rapid synapse formation during are among the most intricate structures cells can build. the first year after birth, the human brain experiences a Their morphogenesis involves growth mechanisms, but steady decrease in synapse density during later develop- also regressive mechanisms like retraction or degener- ment until a plateau is reached at the onset of adulthood ation of supernumerary or non-specific processes. Re- (Huttenlocher, 1990). But it is not only small synapses that gressive mechanisms are collectively known as pruning. can be removed through pruning, but also long stretches Pruning can serve the specification of neuronal circuits or of axon or dendrite. In this review, we discuss four exam- the removal of developmentally intermediate structures. ples of neurite pruning across model organisms in order Pruning can affect both single synapses or long stretches to explain the general features and cell biological mech- of neurite. Here, we introduce well-characterized models anisms of pruning. These examples are: (1) motoneuron of developmental pruning in mammals and Drosophila axon pruning at the mammalian neuromuscular junction, with their presumed purpose, triggers and cell biological (2) pruning of retinal ganglion cell synapses in the higher mechanisms. We will then define general mechanistic fea- order visual system, (3) pruning of corticospinal tract ax- tures of pruning. ons of layer V cortical neurons, and (4) pruning of class Keywords: circuit assembly; neurodegeneration; phago- IV dendritic arborization (c4da) neurons in the fruit fly cytosis Drosophila. Introduction Pruning: circuit specification and The long and often branched processes of neurons, ax- more ons and dendrites, are specialized compartments used Why do neurons build synapses or neurites just to degrade to collect and propagate information, respectively. Infor- them again later on during development? For one, neurons mation is passed on between neurons through synaptic (many billions in the mammalian brain) must make many connections. During development, neurites can grow long highly specific synaptic connections (often thousands for distances towards their respective target areas, and sev- a mammalian neuron in the brain). Accordingly, many eral mechanisms ensure that growing neurites find their specificity pathways are known that guide axons to their proper synaptic targets with high precision. However, correct targets and promote synaptic connections only be- phases of neurite outgrowth are often also followed by tween specific pre- and postsynaptic partners. These sys- phases of neurite removal during development. Such re- tems usually consist of transmembrane receptors and their gressive mechanisms are often collectively referred to as respective ligands on synaptic partners. The diversity of these receptors is relatively high, and is even increased by alternative splicing (some axon guidance receptors have *Corresponding author: Dr. Sebastian Rumpf, Institut für Neuro- und Verhaltensbiologie, Westfälische Wilhelms-Universität Münster, hundreds of splice isoforms). Yet the question arises if the Badestraße 9, 48149 Münster, Germany, E-Mail: sebastian.rumpf@ combinatorial possibilities of a few thousand transmem- uni-muenster.de brane receptors can encode enough specificity for each of Sandra Rode, Institut für Neuro- und Verhaltensbiologie, Westfäli- these many billions of synapses to be purely genetically sche Wilhelms-Universität Münster, Badestraße 9, 48149 Münster, encoded. In other words, errors in connectivity during the Germany Rafael Krumkamp, Institut für Neuro- und Verhaltensbiologie, initial progressive phase of neuronal development might Westfälische Wilhelms-Universität Münster, Badestraße 9, be unavoidable. Subsequent corrective measures such 48149 Münster, Germany as pruning would be required to achieve the connection Svende Herzmann, Institut für Neuro- und Verhaltensbiologie, specificity needed for proper brain function. Alternative- Westfälische Wilhelms-Universität Münster, Badestraße 9, ly, mammalian brain circuit development might actually 48149 Münster, Germany A20 S. Rumpf et al.: Mechanisms of Neurite Pruning involve a trial-and-error mechanism. In such a scenario, ing, and the spatial aspects of the degeneration process the best-suited out of a number of randomly-made synap- are predetermined. Small-scale pruning is usually the re- tic connections would be selected by functional tests, and sult of activity-dependent synapse competition, such that others would be removed. In both scenarios, pruning en- the identity of the pruned synapse or branch is not clear hances the specificity of brain connectivity. from the beginning. Large-scale pruning events are usual- Another case where pruning is necessary are develop- ly involved in the removal of developmental intermediates mental transitions of the nervous system. A good example such as during insect metamorphosis. for this type of pruning are holometabolous insects, whose life cycles are divided into morphologically very distinct larval and adult phases. The nervous system of a fly larva (1) Synapse elimination at the mammalian is adapted to its lifestyle of crawling and eating, while that neuromuscular junction (NMJ) of the adult fly is adapted to flying and reproducing. Many parts of the larval nervous system are useless in adult life At birth, skeletal NMJs in mammals are innervated by and are therefore removed during metamorphosis, the lar- multiple motoneuron axons. During the first two postna- val-to-adult transition. Here, pruning serves the removal tal weeks, motoneuron axon branches are systematically of developmental intermediates. eliminated until each NMJ is only innervated by one mo- A distinction that is often made is between small-scale toneuron axon (Fig. 1A). Pruning axons initially thin out and large-scale pruning. Small-scale pruning refers to the and retract from the NMJ, while the prevailing axon takes pruning of single synapses or small stretches of neurite, over the whole NMJ. Retreating axons often form a charac- whereas large-scale pruning can remove long parts of teristic “retraction bulb” at the end, and they leave behind primary axons or dendrites. Small-scale pruning involves small membrane-bound particles termed axosomes (Bish- retraction as a mechanism, whereas large-scale pruning op et al., 2004). Retraction stops at the next axon branch uses neurite degeneration (i. e., severing and fragmenta- point. tion) as a mechanism. Large-scale pruning tends to be ste- Motoneuron synapses are eliminated by a competitive reotyped, i. e., the identity of the pruned branch, the tim- mechanism. For each NMJ, the presynaptic terminal that Fig. 1: Examples of pruning during mammalian neuronal development. A Synapse elimination at the Neuromuscular junction (NMJ). First, NMJs receive input from multiple motoneurons (MN) (left), weaker axons retract in the following (right). B Eye specific segregation of retinal ganglion cell (RGC) axons in the dorsal Lateral Geniculate Nucleus (dLGN).Target areas of ipsi- and contralateral RGC axons overlap around birth(left), non-specific inputs are eliminated, leading to segregation of target areas (right). C Axon pruning of cortical L5-neurons. L5-neurons from visual and motor cortex project initially both to the spinal cord and to visual centers such as the Superior Colliculus (SC) (left), nonspecific axons degenerate eventually (right). S. Rumpf et al.: Mechanisms of Neurite Pruning A21 releases more neurotransmitter – and hence activates the totic (i. e., dying) cells (Chung et al., 2013). Lack of the muscle better – is stabilized, while the weaker presynaptic above receptors leads to segregation and connectivity terminal is destabilized. This can be mimicked experimen- defects in the dLGN. RGC axon segregation is an exam- tally by activating or inhibiting single axons, which en- ple of small-scale pruning and serves to specify visual hances or decreases their chances of prevailing at the NMJ. circuits. Stabilization and destabilization involve retrograde feed- back from the muscle to the individual presynaptic axon terminals. It has been postulated that mature and imma- (3) Selective elimination of layer V corticos- ture isoforms of Brain-derived Neurotrophic Factor (BDNF) pinal tracts can act as such stabilizing and destabilizing feedback sig- nals, respectively (Je et al., 2012). Weak axon branches are The mammalian neocortex is organized into five layers of systematically destabilized. They contain fewer stabilizing neurons. Pyramidal neurons in layer V (L5) signal cortical cytoskeletal elements, and retraction bulbs contain lyso- output to other regions in the CNS. Layer V neurons from somes (membrane degrading organelles). Axosomes are different cortical areas project axons to different targets: often engulfed by myelinating Schwann cells. NMJ syn- L5 neurons in the visual cortex project to the Superior Col- apse elimination serves to specify muscle inputs and is an liculus (SC), a visual computation center, whereas L5 neu- example of small-scale pruning. rons in the motor cortex project axons to the spinal cord. In mice, L5 neuron axons start to grow around birth.
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