In contrast, a plant cell typically has hundreds of MTOCs, producing girdle-like arrays of microtubules running around the cell's inner periphery.
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Animal Growth Hormones Hormones are produced in the endocrine glands of animals. Meiosis and Alternation of Generations Plants are characterized by having alternation of generations in their life cycles. C In cultured rodent DRG neurons, the centrosome is first situated at the base of one neurite, and at this position Tpx2 facilitates Aurora A activation. In cultured rodent hippocampal neurons, RanGTP becomes concentrated in two positions in every newly forming neurite: one at the base and one in the distal portion.
In cultured rodent DRG neurons, there is a local hand-off of Tpx2-centered nucleation machinery from the centrosome to an acentrosomal site. Initially, the centrosome is located at the base of one neurite, where it generates microtubules.
Then, the centrosome migrates away from this position and at the same time it stops generating microtubules. Microtubule generation within neurites is also triggered concomitant with the passage of actin waves. These are traveling waves of transient local actin reorganization into filopodia and lamellipodia that move slowly along the neurite from its base to its tip Flynn et al.
In cultured rodent hippocampal neurons, a local increase in microtubule generation activity occurs in the wake of the wave Winans et al. Alongside neurite formation, nascent neurons must polarize Schelski and Bradke, ; Yogev and Shen, This is usually into one axon and multiple dendrites, although some specialized neuron types develop other configurations Troutt et al.
Microtubules in the axon are predominantly oriented plus-ends-out, an anterograde organization Baas et al. While in the dendrites of vertebrate neurons microtubules are a mix of minus-ends-out retrograde and plus-ends-out orientations Baas et al.
Importantly, these organizational differences of microtubule polarity direct compartment-specific trafficking of cargo within the neuron Burute and Kapitein, ; Kelliher et al. A complex set of signaling events are used to select one neurite to become the axon Schelski and Bradke, ; Yogev and Shen, Even so, as demonstrated in cultured rodent hippocampal neurons, at the point when one neurite becomes the axon it shows a selective enhancement of stable plus-ends-out microtubules Witte et al.
One process involved in generating and maintaining axon unipolar organization is microtubule sliding Baas and Falnikar, ; Del Castillo et al. A second is microtubule generation through Augmin. In the axon, while there is evidence of a proximal enriched region of microtubule generation in both cultured rodent hippocampal neurons and multiple C.
Figure 2. They locally amplify microtubule generation. Augmin also supports plus-ends-out microtubule generation in the axon. Augmin plays a further specific role in the axon; it maintains the specialized unipolar organization of axon microtubules. A key aspect of Augmin activity described in the spindle of human U2OS cells and in meiotic Xenopus egg extracts is that it nucleates a new microtubule that polymerizes with the same polarity as the host microtubule upon which it was initiated Kamasaki et al.
It is expected that the same mechanism occurs in neurons, and this explains changes in microtubule polarities in the axon when Augmin activity is lost. In the axon all the potential host microtubules are plus-ends-out, and Augmin activity enables newly generated microtubules to maintain this unipolar organization Figure 2.
In contrast to the axon, dendrite differentiation requires the generation of both plus-ends-out and minus-ends-out microtubules. Two recent studies in C. In the dendritic growth cone of the C.
This site at the tip of the extending dendrite is an MTOC that produces both anterograde and retrograde polymerizing microtubule populations; these create the plus-ends-out and minus-ends-out microtubule arrays of the dendrite, respectively Figure 3A. Compared to the minus-ends-out population, the plus-ends-out microtubules that are generated from the tip MTOC pause longer between polymerization and depolymerization. When a sufficient plus-ends-out array is established, the MTOC moves toward the tip so that it tracks tip extension.
Moreover, as Kinesin-1 prefers to move on stable microtubules, which are the plus end out population, these data suggest a model in which Kinesin-1 is engaged to move the MTOC along this plus-ends-out array so that it tracks tip extension Liang et al.
Figure 3. When the MTOC is mislocalized to the soma, all microtubules in the dendrite are now plus-ends-out. B Sites of MTOC activity in late stage neurons, illustrated for the combined data from multiple studies in Drosophila da neurons. These generate a population of polymerizing microtubules that exclusively invade the axon.
Golgi may also act as local site of microtubule generation at the branchpoints of a nascent branch. During primary dendrite outgrowth, a network of actin regulators centered around the actin motor Myosin6 set both the position and direction of the microtubule polymerization events generated from a dendritic growth cone MTOC.
Furthermore, this MTOC is utilized in the splitting of the tip into new primary branches. Splitting correlates with surges in the generation of the anterograde polymerizing population; these anterograde polymerizing microtubules are then guided into nascent branches via retrograde extension of actin filaments at the base of growth cone filopodia Yoong et al. The growth cone MTOC at the tip of a growing dendrite is a developmental structure required to create and organize the microtubules of the primary dendrite arbor branches; a different kind of tip MTOC is found in some specialized mature sensory neurons Harterink et al.
These sensory neuron types have a single dendrite tipped with a sensory cilium Troutt et al. At the base of cilia is a basal body, which is created from a centriole that is reutilized after the centrosome has been decommissioned, and imaging of differentiating C. Multiple C. In contrast, in those types with a dedicated MTOC at the base of the cilia, the transport remains efficient along the length of the dendrite Harterink et al. Dendritic growth cone MTOCs play a role in the formation of primary branch structure.
However, neurons pattern through an evolving set of processes rather than repetitive use of a single set of local cell biological operations Yoong et al. For the formation of high order branches, different processes are required.
In multiple models including rodent hippocampal and cortical neurons, chick DRG neurons and Drosophila da neurons, high order branches form interstitial pioneer filopodia and lamellipodia that are then stabilized by the invasion of microtubules Kalil and Dent, In dendrites, microtubule invasion from the main dendrite trunk into higher order compartments occurs in differentiation processes, such the formation of terminal branches in Drosophila da neurons or spines in rodent hippocampal neuron cultures Gu et al.
It also occurs in activity-dependent spine remodeling in the mature neurons, as shown in rodent hippocampal neuron cultures and slice cultures Hu et al. This activity-dependent invasion of microtubules creates tracks for motor-mediated transport of synaptic cargo into the spine Esteves da Silva et al. Based on recent data, it is interesting to speculate that actin reorganization to form a microtubule-capturing structure is a commonality between developmental and activity-dependent microtubule invasion processes.
During major dendrite branching in Drosophila da neurons, extension of the tail of a subset of actin filaments toward the center of the dendrite growth cone is used to regulate the capture and guidance of polymerizing microtubules into filopodia Yoong et al. In rodent hippocampal neuron cultures and slice cultures, spine activation leads to Cortactin-mediated projection of actin filaments into the main dendrite trunk from the base of the spine, and these filaments guide microtubules polymerizing along the main dendrite to turn into and invade the spine Schatzle et al.
Drosophila da sensory neurons have been the major model used to study how and where microtubules are generated for late-stage dendrite branching processes. Local focal sites of microtubule generation at branchpoints contribute to invading microtubules Ori-McKenney et al. In the mature stage, the branchpoint-associated sites continue to generate microtubules and are important for maintaining the minus-ends-out organization of the dendrites Nguyen et al.
While it remains possible that there are changes in branchpoint site operation from the period of late-stage branching through into the mature neuron state, present data does not indicate that they are different.
Dendrites contain fragments of Golgi stacks named Golgi outposts, as show in rat hippocampal neurons and Drosophila neurons Horton and Ehlers, ; Ori-McKenney et al.
In several non-neuronal mammalian cell types Golgi stacks nucleate microtubules Martin and Akhmanova, ; Akhmanova and Steinmetz, ; Valenzuela et al. Golgi outposts also organize microtubules in the branches of rodent oligodendrocytes. Unidirectional microtubule generation was shown to be promoted from outposts in Drosophila sensory da neurons by Plp, Cnn, and GM Ori-McKenney et al.
Overall, these studies led to a model in which an outpost MTOC generates a unipolar train of microtubules which controls the local balance of anterograde and retrograde microtubules, and this activity alters the probability that a local nascent branch invaded and stabilized into a bona fide branch Delandre et al. However, this model is not supported by all findings. In mature Drosophila da neurons, the main site of Golgi-mediated microtubule generation was shown to be from stacks in the soma, which generate a population of microtubules that exclusively invade the axon Mukherjee et al.
Therefore, there must be additional platforms for high order branch-related MTOC assembly. In both Drosophila da neurons and C. Disrupting the activity of several Wnt signaling proteins alters the overall balance of microtubule polarity in the dendrites Weiner et al. In Drosophila da neuron dendrites, Dvl and Axin localize at branchpoint endosomes. Neurons develop specific architectures to support their functional requirements; one way in which this manifests is in the organization of their microtubule cytoskeleton.
The stereotyped patterns of dendrite and axon arbors are genetically encoded by transcription factors Jinushi-Nakao et al. One way by which these transcription factors regulate arbor patterning is through controlling the expression of cytoskeleton regulators including factors that control MTOC activity. This has been shown in Drosophila da neurons, which are excellent models in which to address how differentiation processes are modified to create neurons with distinct morphologies.
They exist in four principal types named c1da—c4da in order of increasing complexity in their characteristic dendrite arbor shapes, and these characteristic shapes are defined through da neuron type-specific transcription factor codes Dong et al. An interaction between this Cnn activity and Augmin activity sets the frequency at which polymerizing microtubules invade nascent branches Yalgin et al. Because neuron morphogenesis is a compound process Hassan and Hiesinger, ; Yoong et al.
In Drosophila da neurons, changing the frequency at which polymerizing microtubules invade nascent branches correlates with branch outgrowth, and ultimately with arbor final branch number Ori-McKenney et al.
Another example of transcription factor mediated regulation occurs at the dendrite tip MTOC in Drosophila da neurons. In knot mutants the tip MTOC becomes disorganized; more microtubules are generated in the periphery of the dendritic growth cone and they polymerize in a retrograde direction rather than an anterograde direction.
Knot-mediated regulation of the tip MTOC activity occurs in part through upregulating the expression of Myosin6. Ultimately, changing Knot and Myosin6 activity correlates with altered major branch frequency in the arbor Yoong et al. To fully understand the fundamental mechanisms that create form and function in nervous systems requires that investigators not only identify the components of the neuron differentiation process, but also understand the operational control mechanisms that direct and shape their usage.
Understanding how diversity in MTOC organization arises between neuron types can be a powerful way to reveal operational controls over the neuron differentiation process at the systems level. In Drosophila da neurons, Patronin binds to the minus-ends and promotes their polymerization.
This allows the minus-ends to grow in an anterograde direction into dendrite branches to boost the minus-ends-out population in this compartment Feng et al. Microtubule severing proteins such as Katanin and Spastin fragment pre-existing microtubules. This creates new local seeds and catalyzes microtubule formation Vemu et al.
In rodent hippocampal neurons and Drosophila da and motoneurons, the activity of these microtubule severing proteins shapes outgrowth and branching in both axon and dendrite compartments Jinushi-Nakao et al. While centrosomal and acentrosomal MTOC factors have been systematically examined in postmitotic neurons, it is likely that important non-canonical microtubule generation processes remain to be discovered.
SSNA1 localizes at axon branchpoints in cultured rodent hippocampal neurons. In vitro it drives the forking of pre-existing microtubules to induce branch formation. These in vitro studies show that SSNA1 fibrils lie along the side of a microtubule, where they guide a subset of parental microtubule protofilaments to splay out.
The splayed protofilaments seed a microtubule branch Basnet et al. A further potential new mechanism is based on how centrosomes increase in microtubule generation capacity at the onset of mitosis. Homotypic protein-protein interactions between scaffolding proteins Drosophila Cnn or C. This compartment captures and concentrates Tubulin from the surrounding environment to stimulate local microtubule production Feng et al. Mammalian Tau is a neuronal candidate for this model of nucleation activity.
Moreover, it organizes the resultant microtubules to resemble their bundled organization in axons Hernandez-Vega et al. Whether this process functions in in vivo remains to be determined. The studies described here show how several distinct mechanisms for microtubule generation occur in the neurons. Recent studies in invertebrates have found endosomes are one platform upon which a dendrite MTOC can be established Liang et al.
There is conflicting evidence whether Golgi outposts are another Ori-McKenney et al. Just as neuron polarization mechanisms differ between neuron types due to intrinsic programming and interplay with the local environment Yogev and Shen, , the same is likely for neuron microtubule generation mechanisms—with an added critical dimension that the sites and mechanisms of microtubule generation shift as the neuron proceeds along its differentiation trajectory. Importantly, control mechanisms that regulate these critical transitions in MTOC mechanism are presently unknown; this key question is now opening for analysis.
A further challenge is to consider how distinct neuronal MTOC mechanisms operate and interact at the systems level. The field will benefit from new generations of cell biologically informed computational models of differentiation to aid this Goodhill, Crucially, understanding how individual microtubule generation mechanisms combine to delineate mature neuron function requires detailed long-term imaging of the cell biological events underlying arbor differentiation, with quantitative analyses of these events.
Neurons respond to injury with upregulation of microtubule generation in the axons and dendrites, as shown in Drosophila da neurons, C. One role of this is as a signal that upregulates neuroprotective programs, as demonstrated in Drosophila da neurons Chen et al.
In addition, damaged axon stumps form into a disorganized retraction bulb, which must then be converted into a functional growth cone to regrow.
In rodent axon regeneration after spinal cord injury, mild pharmacological stabilization of axon tip microtubules helps to enhance this conversion Hellal et al. A nuanced balance between dynamic and stable microtubules is required to stimulate axon regrowth Blanquie and Bradke, and studies in Drosophila and C. Beyond understanding differentiation, the discovery and elucidation of new neuronal microtubule nucleation pathways also provides potential targets for drug development to promote nervous system repair Blanquie and Bradke, In summary, an unfolding series of cell biological morphogenetic processes create final neuronal pattern Hassan and Hiesinger, ; Yoong et al.
In this review we have highlighted how molecularly distinct MTOC mechanisms create microtubules during these different stages of differentiation, and we have shown how temporal and spatial organization of these mechanisms are used to pattern and diversify dendrite and axon arbor wiring. OW and AM: concept and wrote, and edited the manuscript. Both authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Akhmanova, A. Microtubule minus-end regulation at a glance. Cell Sci. Baas, P. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Baird, D.
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