Mapping axon initial segment structure and function by multiplexed proximity biotinylation

Hamdan, Hamdan; Lim, Brian C.; Torii, Tomohiro; Joshi, Abhijeet; Konning, Matthias; Cw, Smith; Palmer, D. Jason; Ng, Philip; Leterrier, Christophe; Oses-Prieto, Juan A.; Burlingame, Alma L.; Rasband, Matthew N.

doi:10.1038/s41467-019-13658-5

Cited by 79 publications

(98 citation statements)

References 67 publications

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“…such as lamellipodia and filopodia, under all different experimental conditions tested. This level of specificity likely requires the use of accessory protein [55][56][57] interaction with specific phospholipid domains 58 and/or dynamic association-dissociation mechanisms of spectrin-actin bonds instrumental for membrane stability and trafficking 59 .…”

Section: Discussionmentioning

confidence: 99%

Complementary mesoscale dynamics of spectrin and acto-myosin shape membrane territories during mechanoresponse

et al. 2020

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The spectrin-based membrane skeleton is a major component of the cell cortex. While expressed by all metazoans, its dynamic interactions with the other cortex components, including the plasma membrane or the acto-myosin cytoskeleton, are poorly understood. Here, we investigate how spectrin re-organizes spatially and dynamically under the membrane during changes in cell mechanics. We find spectrin and acto-myosin to be spatially distinct but cooperating during mechanical challenges, such as cell adhesion and contraction, or compression, stretch and osmolarity fluctuations, creating a cohesive cortex supporting the plasma membrane. Actin territories control protrusions and contractile structures while spectrin territories concentrate in retractile zones and low-actin density/inter-contractile regions, acting as a fence that organize membrane trafficking events. We unveil here the existence of a dynamic interplay between acto-myosin and spectrin necessary to support a mesoscale organization of the lipid bilayer into spatially-confined cortical territories during cell mechanoresponse.

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Section: Discussionmentioning

confidence: 99%

Complementary mesoscale dynamics of spectrin and acto-myosin shape membrane territories during mechanoresponse

et al. 2020

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“…Interestingly, our data suggests that elongation only occurs at the distal end of the AIS, which requires protein biosynthesis and axonal transport of the macromolecular complexes via the microtubule network towards the distal site, and subsequent protein assembly (Freal et al, 2019). This energetically "expensive" task is presumably time-consuming, particularly considering the vast downstream network of molecular binding partners localized in the AIS (Hamdan et al, 2020).…”

Section: Bidirectional Temporally Diverse Forms Of Ais Plasticitymentioning

confidence: 90%

Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex

Jamann

Dannehl

Wagener

et al. 2020

Preprint

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The axon initial segment (AIS) is an important axonal microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent cortical plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using an in vivo model of the mouse whisker-to-barrel pathway in combination with immunofluorescence, confocal analysis and patch-clamp electrophysiological recordings, we observed bidirectional AIS plasticity. Furthermore, we find that structural and functional AIS remodeling occurs in distinct temporal domains: long-term sensory deprivation elicits an AIS length increase, accompanied with an increase in neuronal excitability, while sensory enrichment results in a rapid AIS shortening, accompanied by a decrease in action potential generation. Our findings highlight a central role of the AIS in the homeostatic regulation of neuronal inputoutput relations.

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“…Although remarkable progress has been made in uncovering the roles of ankyrins and spectrins as principal actors in the AIS, we do not fully understand how they integrate into the developing model of AIS plasticity and its relevance to disease (Sohn et al, ). Technical advances, such as AIS‐targeted proteomics (Hamdan et al, ), should enable us to gain deeper insights into the organization and function of AIS. As we continue to learn more about axonal functions of these molecules, it is important that we prioritize research on their understudied dendritic roles.…”

Section: Perspectivesmentioning

confidence: 99%

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Lorenzo

2020

Cytoskeleton

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The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long‐range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self‐assemble with both remarkable long‐range regularity and micro‐ and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.

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Mapping axon initial segment structure and function by multiplexed proximity biotinylation

Cited by 79 publications

References 67 publications

Complementary mesoscale dynamics of spectrin and acto-myosin shape membrane territories during mechanoresponse

Complementary mesoscale dynamics of spectrin and acto-myosin shape membrane territories during mechanoresponse

Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

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