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Fig. 3 | Neural Development

Fig. 3

From: The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

Fig. 3

An interactome of MT-regulating and -associated mechanisms expected to contribute within the model of local axon homeostasis. Developing and mature neurons are shown at the bottom indicating that the close-up (magenta frame) might apply in both contexts. 1-16) Potential mechanisms that can 'tame' MTs into bundled conformation: MT polymerisation (blue stippled arrows) is driven by molecular machinery centred on Eb1 (blue balls), further influenced by the tubulin supply machinery (not shown) and shaft-binding proteins (7); polymerisation generates new MTs required for bundle formation (8) and turn-over (14); to integrate into bundles, extending MTs require guidance via actin-Eb1 cross-linkage along the axonal surface (5; Shot) or along pre-existing MTs through MT-MT cross-linkers (9; brown L). The same or other cross-linkers provide the structural glue that holds MT bundles together (12; brown L); some of them can also bind to actin (2), they protect from (or recruit) MT severing activity (15), and influence motor protein dynamics (a). MTs which have escaped any cross-linkage are inhibited by cortical collapse factors when approaching the axonal surface (4; Efa6) or by MT-severing factors at MT-MT cross-points (6). The bundled MTs are discontinuous; their free minus ends are stabilised by CAMSAP/Patronin (Ptrn) together with katanin (black scissors; 13), whereas non-polymerising MT plus ends are stabilised by other factors (not shown; e.g. CLASP or the Dynactin subunit p150/Glued [404, 405]). The dynein/Dynactin complex is believed to link cortical actin to MT bundles and drive them anterogradely (10), whereas Ptrn at minus ends may anchor MTs via spectraplakins to the axon cortex (1); spectraplakins may also link MTs directly to cortical actin (2) or to transmembrane receptors (3), and they are expected to perform further, still unexplored actin-independent bundle-promoting roles through their PRR domains (11). Tear-and-wear damages MTs (dashed green line), potentially affecting interaction with MT-binding proteins (16; red X); MT severing proteins might selectively eliminate such MTs (16; scissors), or MTs undergo repair (not shown). Nucleation of MTs (17) is mediated by ɣTuRC directionally anchored to MT lattices via the augmin/HAUS complex (AUG). A-E) Mechanisms closely 'associated' with MT bundles: MT-associated motor proteins ('motor', solid orange arrows) drive axonal transport of (protein-loaded) vesicles (A), cytoplasmic factors including proteins, translational machinery (ribosomes) or RNAs (B), move other MTs (B, sliding), and position/rearrange organelles including mitochondria (C, mitos), endoplasmic reticulum, peroxisomes and endosome (D) - and this likely includes mitochondrial fission and fusion (E). a-e) The motor-associated functions all act downstream of MT bundles because they require them to walk on; but they also act upstream: for example, the forces they generate (stippled orange arrows) are the potential cause for MT disorganisation (buckling shown in d); transport delivers important regulators and building blocks for bundle-maintaining processes (b); the proper regulation of organelles/endocytic compartments provides systemic factors that can orchestrate MT bundle-taming mechanisms, including intracellular free calcium or reactive oxygen species (Ca2+, ROS; yellow cloud [202, 203]) as well as ATP required for many processes including actin dynamics, MT severing and MT motor activity (red stippled arrows; note that vesicular transport uses glycolysis to generate its own ATP; yellow star); vice versa, the MT severer spastin also regulates the ER through ATP-independent mechanisms (e), and MT-associated proteins (APC) regulate local translation events (c)

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