One of the characteristic features of different classes of neurons that is vital for their proper functioning within neuronal networks is the shape of their dendritic arbors. To properly develop dendritic trees, neurons need to accurately control the intracellular transport of various cellular cargo (e.g., mRNA, proteins, and organelles). Microtubules and motor proteins (e.g., dynein and kinesins) that move along microtubule tracks play an essential role in cargo sorting and transport to the most distal ends of neurons. Equally important are motor adaptors, which may affect motor activity and specify cargo that is transported by the motor. Such transport undergoes very dynamic fine-tuning in response to changes in the extracellular environment and synaptic transmission. Such regulation is achieved by the phosphorylation of motors, motor adaptors, and cargo, among other mechanisms. This review focuses on the contribution of the dynein-dynactin complex, kinesins, their adaptors, and the phosphorylation of these proteins in the formation of dendritic trees by maturing neurons. We primarily review the effects of the motor activity of these proteins in dendrites on dendritogenesis. We also discuss less anticipated mechanisms that contribute to dendrite growth, such as dynein-driven axonal transport and non-motor functions of kinesins.
The endocytic adaptor protein 2 (AP-2) complex binds dynactin as part of its noncanonical function, which is necessary for dynein-driven autophagosome transport along microtubules in neuronal axons. The absence of this AP-2-dependent transport causes neuronal morphology simplification and neurodegeneration. The mechanisms that lead to formation of the AP-2-dynactin complex have not been studied to date. However, inhibition of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) enhances the transport of newly formed autophagosomes, by influencing the biogenesis and protein interactions of Rab-interacting lysosomal protein (RILP), another dynein cargo adaptor. We tested the effects of mTORC1 inhibition on interactions between the AP-2 and dynactin complexes, with a focus on their two essential subunits, AP-2β and p150Glued. We found that the mTORC1 inhibitor rapamycin enhanced AP-2-dynactin complex formation in both neurons and non-neuronal cells. The live imaging of neuronal axons revealed that when combined with brain-derived neurotrophic factor (BDNF), an agonist of tropomyosin receptor kinase B (TrkB), rapamycin also increased the number of retrogradely moving mobile AP-2β-p150Glued complexes. Additional analysis revealed that the AP-2β-p150Glued interaction was indirect and required integrity of the dynactin complex. Rapamycin-driven enhancement of the AP-2-dynactin interaction also required the presence of cytoplasmic linker protein 170 (CLIP-170) and activation of autophagy. The latter was sufficient to enhance the AP-2β interaction with p150Glued, even when mTORC1 was active. Altogether, our results show that autophagy regulates the AP-2-dynactin interaction to coordinate sufficient motor-adaptor availability for newly generated autophagosomes.
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