Visiting Investigators

Permanent URI for this collection

https://hdl.handle.net/1912/116

Scores of distinguished biologists from around the world come to the MBL to collaborate and conduct research. They use marine and other organisms as model systems for their research.

These researchers participate in a number of established MBL groups including but not limited to:

  • MBL Summer Research Fellows
  • Dart Scholars
  • Grass Faculty Awardees
  • NeuroImaging Cluster
  • Grass Fellows
  • Whitman Center

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Browsing Visiting Investigators by Title

  • Article
    A complete biomechanical model of Hydra contractile behaviors, from neural drive to muscle to movement
    (National Academy of Sciences, 2023-03-14) Wang, Hengji ; Swore, Joshua ; Sharma, Shashank ; Szymanski, John R. ; Yuste, Rafael ; Daniel, Thomas L. ; Regnier, Michael ; Bosma, Martha M. ; Fairhall, Adrienne L.
    How does neural activity drive muscles to produce behavior? The recent development of genetic lines inthat allow complete calcium imaging of both neuronal and muscle activity, as well as systematic machine learning quantification of behaviors, makes this small cnidarian an ideal model system to understand and model the complete transformation from neural firing to body movements. To achieve this, we have built a neuromechanical model of's fluid-filled hydrostatic skeleton, showing how drive by neuronal activity activates distinct patterns of muscle activity and body column biomechanics. Our model is based on experimental measurements of neuronal and muscle activity and assumes gap junctional coupling among muscle cells and calcium-dependent force generation by muscles. With these assumptions, we can robustly reproduce a basic set of's behaviors. We can further explain puzzling experimental observations, including the dual timescale kinetics observed in muscle activation and the engagement of ectodermal and endodermal muscles in different behaviors. This work delineates the spatiotemporal control space of movement and can serve as a template for future efforts to systematically decipher the transformations in the neural basis of behavior.
  • Article
    A gene duplication of a septin reveals a developmentally regulated filament length control mechanism
    (Rockefeller University Press, 2023-02-14) Cannon, Kevin S ; Vargas-Muniz, Jose M. ; Billington, Neil ; Seim, Ian ; Ekena, Joanne ; Sellers, James R. ; Gladfelter, Amy S.
    Septins are a family of conserved filament-forming proteins that function in multiple cellular processes. The number of septin genes within an organism varies, and higher eukaryotes express many septin isoforms due to alternative splicing. It is unclear if different combinations of septin proteins in complex alter the polymers' biophysical properties. We report that a duplication event within the CDC11 locus in Ashbya gossypii gave rise to two similar but distinct Cdc11 proteins: Cdc11a and Cdc1b. CDC11b transcription is developmentally regulated, producing different amounts of Cdc11a- and Cdc11b-complexes in the lifecycle of Ashbya gossypii. Deletion of either gene results in distinct cell polarity defects, suggesting non-overlapping functions. Cdc11a and Cdc11b complexes have differences in filament length and membrane-binding ability. Thus, septin subunit composition has functional consequences on filament properties and cell morphogenesis. Small sequence differences elicit distinct biophysical properties and cell functions of septins, illuminating how gene duplication could be a driving force for septin gene expansions seen throughout the tree of life.
  • Article
    Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation
    (EMBO Press, 2019-12-27) Trotschel, Christian ; Hamzeh, Hussein ; Alvarez, Luis ; Pascal, René ; Lavryk, Fedir ; Bönigk, Wolfgang ; Körschen, Heinz Gerd ; Müller, Astrid ; Poetsch, Ansgar ; Rennhack, Andreas ; Gui, Long ; Nicastro, Daniela ; Strünker, Timo ; Seifert, Reinhard ; Kaupp, U. Benjamin
    Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca2+ rise that controls motility. The mechanisms underlying such ultra‐sensitivity are ill‐defined. Here, we determine by mass spectrometry the copy number of nineteen chemosensory signaling proteins in sperm flagella from the sea urchin Arbacia punctulata. Proteins are up to 1,000‐fold more abundant than the free cellular messengers cAMP, cGMP, H+, and Ca2+. Opto‐chemical techniques show that high protein concentrations kinetically compartmentalize the flagellum: Within milliseconds, cGMP is relayed from the receptor guanylate cyclase to a cGMP‐gated channel that serves as a perfect chemo‐electrical transducer. cGMP is rapidly hydrolyzed, possibly via “substrate channeling” from the channel to the phosphodiesterase PDE5. The channel/PDE5 tandem encodes cGMP turnover rates rather than concentrations. The rate‐detection mechanism allows continuous stimulus sampling over a wide dynamic range. The textbook notion of signal amplification—few enzyme molecules process many messenger molecules—does not hold for sperm flagella. Instead, high protein concentrations ascertain messenger detection. Similar mechanisms may occur in other small compartments like primary cilia or dendritic spines.
  • Article
    Activity-dependent Golgi satellite formation in dendrites reshapes the neuronal surface glycoproteome
    (eLife Sciences Publications, 2021-09-21) Govind, Anitha P. ; Jeyifous, Okunola ; Russell, Theron A. ; Yi, Zola ; Weigel, Aubrey V. ; Ramaprasad, Abhijit ; Newell, Luke ; Ramos, William ; Valbuena, Fernando M. ; Casler, Jason C. ; Yan, Jing-Zhi ; Glick, Benjamin S. ; Swanson, Geoffrey T. ; Lippincott-Schwartz, Jennifer ; Green, William N.
    Activity-driven changes in the neuronal surface glycoproteome are known to occur with synapse formation, plasticity, and related diseases, but their mechanistic basis and significance are unclear. Here, we observed that N-glycans on surface glycoproteins of dendrites shift from immature to mature forms containing sialic acid in response to increased neuronal activation. In exploring the basis of these N-glycosylation alterations, we discovered that they result from the growth and proliferation of Golgi satellites scattered throughout the dendrite. Golgi satellites that formed during neuronal excitation were in close association with endoplasmic reticulum (ER) exit sites and early endosomes and contained glycosylation machinery without the Golgi structural protein, GM130. They functioned as distal glycosylation stations in dendrites, terminally modifying sugars either on newly synthesized glycoproteins passing through the secretory pathway or on surface glycoproteins taken up from the endocytic pathway. These activities led to major changes in the dendritic surface of excited neurons, impacting binding and uptake of lectins, as well as causing functional changes in neurotransmitter receptors such as nicotinic acetylcholine receptors. Neural activity thus boosts the activity of the dendrite’s satellite micro-secretory system by redistributing Golgi enzymes involved in glycan modifications into peripheral Golgi satellites. This remodeling of the neuronal surface has potential significance for synaptic plasticity, addiction, and disease.
  • Article
    Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea
    (eLife Sciences Publications, 2020-05-12) Marconi, Aleksandra ; Hancock-Ronemus, Amy ; Gillis, J. Andrew
    Mammalian articular cartilage is an avascular tissue with poor capacity for spontaneous repair. Here, we show that embryonic development of cartilage in the skate (Leucoraja erinacea) mirrors that of mammals, with developing chondrocytes co-expressing genes encoding the transcription factors Sox5, Sox6 and Sox9. However, in skate, transcriptional features of developing cartilage persist into adulthood, both in peripheral chondrocytes and in cells of the fibrous perichondrium that ensheaths the skeleton. Using pulse-chase label retention experiments and multiplexed in situ hybridization, we identify a population of cycling Sox5/6/9+ perichondral progenitor cells that generate new cartilage during adult growth, and we show that persistence of chondrogenesis in adult skates correlates with ability to spontaneously repair cartilage injuries. Skates therefore offer a unique model for adult chondrogenesis and cartilage repair and may serve as inspiration for novel cell-based therapies for skeletal pathologies, such as osteoarthritis.
  • Article
    Affinity purification of label-free tubulins from xenopus egg extracts
    (Cell Press, 2020-12-18) Reusch, Sebastian ; Biswas, Abin ; Hirst, William G. ; Reber, Simone
    Cytoplasmic extracts from unfertilized Xenopus eggs have made important contributions to our understanding of microtubule dynamics, spindle assembly, and scaling. Until recently, these in vitro studies relied on the use of heterologous tubulin. This protocol allows for the purification of physiologically relevant Xenopus tubulins in milligram yield, which are a complex mixture of isoforms with various post-translational modifications. The protocol is applicable to any cell or tissue of interest. For complete details on the use and execution of this protocol, please refer to Hirst et al. (2020).
  • Article
    An algorithm to estimate unsteady and quasi-steady pressure fields from velocity field measurements
    (Company of Biologists, 2013-10-10) Dabiri, John O. ; Bose, Sanjeeb ; Gemmell, Brad J. ; Colin, Sean P. ; Costello, John H.
    We describe and characterize a method for estimating the pressure field corresponding to velocity field measurements such as those obtained by using particle image velocimetry. The pressure gradient is estimated from a time series of velocity fields for unsteady calculations or from a single velocity field for quasi-steady calculations. The corresponding pressure field is determined based on median polling of several integration paths through the pressure gradient field in order to reduce the effect of measurement errors that accumulate along individual integration paths. Integration paths are restricted to the nodes of the measured velocity field, thereby eliminating the need for measurement interpolation during this step and significantly reducing the computational cost of the algorithm relative to previous approaches. The method is validated by using numerically simulated flow past a stationary, two-dimensional bluff body and a computational model of a three-dimensional, self-propelled anguilliform swimmer to study the effects of spatial and temporal resolution, domain size, signal-to-noise ratio and out-of-plane effects. Particle image velocimetry measurements of a freely swimming jellyfish medusa and a freely swimming lamprey are analyzed using the method to demonstrate the efficacy of the approach when applied to empirical data.
  • Article
    All-optical mapping of barrel cortex circuits based on simultaneous voltage-sensitive dye imaging and channelrhodopsin-mediated photostimulation
    (SPIE, 2015-03-31) Lo, Shun Qiang ; Koh, Dawn X. P. ; Sng, Judy C. G. ; Augustine, George J.
    We describe an experimental approach that uses light to both control and detect neuronal activity in mouse barrel cortex slices: blue light patterned by a digital micromirror array system allowed us to photostimulate specific layers and columns, while a red-shifted voltage-sensitive dye was used to map out large-scale circuit activity. We demonstrate that such all-optical mapping can interrogate various circuits in somatosensory cortex by sequentially activating different layers and columns. Further, mapping in slices from whisker-deprived mice demonstrated that chronic sensory deprivation did not significantly alter feedforward inhibition driven by layer 5 pyramidal neurons. Further development of voltage-sensitive optical probes should allow this all-optical mapping approach to become an important and high-throughput tool for mapping circuit interactions in the brain.
  • Article
    ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
    (Nature Publishing Group, 2017-03-08) Sama, Reddy Ranjith K. ; Fallini, Claudia ; Gatto, Rodolfo ; McKeon, Jeanne E. ; Song, Yuyu ; Rotunno, Melissa S. ; Penaranda, Saul ; Abdurakhmanov, Izrail ; Landers, John E. ; Morfini, Gerardo A. ; Brady, Scott T. ; Bosco, Daryl A.
    Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.
  • Preprint
    Ambiguities in the relationship between gonadal steroids and reproduction in axolotls (Ambystoma mexicanum)
    ( 2011-11-01) Eisthen, Heather L. ; Krause, Brianne Chung
    Axolotls (Ambystoma mexicanum) are aquatic salamanders that are widely used in research. Axolotls have been bred in laboratories for nearly 150 years, yet little is known about the basic biology of reproduction in these animals. We investigated the effects of changing day length, time of year, and food availability on levels of circulating estradiol and androgens in adult female and male axolotls, respectively. In addition, we examined the effects of these variables on the mass of ovaries, oviducts, and eggs in females and on mass of testes in males relative to each individual's body weight, to calculate a form of gonadosomatic index (GSI). In both sexes, GSI was not correlated with levels of circulating steroids. In female axolotls, estradiol levels were influenced by food availability, changes in day length, and season, even when animals were held at a constant temperature and day length was decorrelated with calendar date. In addition, the mass of ovaries, oviducts, and eggs varied seasonally, peaking in the winter months and declining during the summer months, even though our animals were not breeding and shedding eggs. In males, levels of androgens appeared to vary independently of external conditions, but GSI varied dramatically with changes in day length. These results suggest that reproduction in axolotls may vary seasonally, as it does in many other ambystomid species, although both male and female axolotls are capable of reproducing several times each year. The physiological basis of this ability remains enigmatic, given the indications of seasonality contained in our data.
  • Preprint
    The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity
    ( 2008-04) LaPointe, Nichole E. ; Morfini, Gerardo A. ; Pigino, Gustavo F. ; Gaisina, Irina N. ; Kozikowski, Alan P. ; Binder, Lester I. ; Brady, Scott T.
    The neuropathology of Alzheimer’s disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dyneindependent FAT rates evaluated by video microscopy. While perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
  • Article
    Aminoglycoside-induced damage in the statocyst of the longfin inshore squid, Doryteuthis pealeii
    (Marine Biological Laboratory, 2014-08-01) Scharr, Alexandra L. ; Mooney, T. Aran ; Schweizer, Felix E. ; Ketten, Darlene R.
    Squid are a significant component of the marine biomass and are a long-established model organism in experimental neurophysiology. The squid statocyst senses linear and angular acceleration and is the best candidate for mediating squid auditory responses, but its physiology and morphology are rarely studied. The statocyst contains mechano-sensitive hair cells that resemble hair cells in the vestibular and auditory systems of other animals. We examined whether squid statocyst hair cells are sensitive to aminoglycosides, a group of antibiotics that are ototoxic in fish, birds, and mammals. To assess aminoglycoside-induced damage, we used immunofluorescent methods to image the major cell types in the statocyst of longfin squid (Doryteuthis pealeii). Statocysts of live, anesthetized squid were injected with either a buffered saline solution or neomycin at concentrations ranging from 0.05 to 3.0 mmol l−1. The statocyst hair cells of the macula statica princeps were examined 5 h post-treatment. Anti-acetylated tubulin staining showed no morphological differences between the hair cells of saline-injected and non-injected statocysts. The hair cell bundles of the macula statica princeps in aminoglycoside-injected statocysts were either missing or damaged, with the amount of damage being dose-dependent. The proportion of missing hair cells did not increase at the same rate as damaged cells, suggesting that neomycin treatment affects hair cells in a nonlethal manner. These experiments provide a reliable method for imaging squid hair cells. Further, aminoglycosides can be used to induce hair cell damage in a primary sensory area of the statocyst of squid. Such results support further studies on loss of hearing and balance in squid.
  • Article
    Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition
    (Elsevier, 2016-07-29) Cox, Kristine ; Combs, Benjamin ; Abdelmesih, Brenda ; Morfini, Gerardo A. ; Brady, Scott T. ; Kanaan, Nicholas M.
    Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.
  • Article
    Ancestry of motor innervation to pectoral fin and forelimb
    (Nature Publishing Group, 2010-07-27) Ma, Leung-Hang ; Gilland, Edwin ; Bass, Andrew H. ; Baker, Robert
    Motor innervation to the tetrapod forelimb and fish pectoral fin is assumed to share a conserved spinal cord origin, despite major structural and functional innovations of the appendage during the vertebrate water-to-land transition. In this paper, we present anatomical and embryological evidence showing that pectoral motoneurons also originate in the hindbrain among ray-finned fish. New and previous data for lobe-finned fish, a group that includes tetrapods, and more basal cartilaginous fish showed pectoral innervation that was consistent with a hindbrain-spinal origin of motoneurons. Together, these findings support a hindbrain–spinal phenotype as the ancestral vertebrate condition that originated as a postural adaptation for pectoral control of head orientation. A phylogenetic analysis indicated that Hox gene modules were shared in fish and tetrapod pectoral systems. We propose that evolutionary shifts in Hox gene expression along the body axis provided a transcriptional mechanism allowing eventual decoupling of pectoral motoneurons from the hindbrain much like their target appendage gained independence from the head.
  • Article
    Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses
    (Nature Research, 2021-01-29) Li, Shuo ; Raychaudhuri, Sumana ; Lee, Stephen Alexander ; Brockmann, Marisa M. ; Wang, Jing ; Kusick, Grant ; Prater, Christine ; Syed, Sarah ; Falahati, Hanieh ; Ramos, Raul ; Bartol, Tomas M. ; Hosy, Eric ; Watanabe, Shigeki
    Neurotransmitter is released synchronously and asynchronously following an action potential. Our recent study indicates that the release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center in mouse hippocampal synapses. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release can lead to maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are likely organized to activate NMDA receptors efficiently.
  • Article
    Athletic equipment microbiota are shaped by interactions with human skin
    (BioMed Central, 2015-06-19) Wood, Mariah ; Gibbons, Sean M. ; Lax, Simon ; Eshoo-Anton, Tifani W. ; Owens, Sarah M. ; Kennedy, Suzanne ; Gilbert, Jack A. ; Hampton-Marcell, Jarrad T.
    Americans spend the vast majority of their lives in built environments. Even traditionally outdoor pursuits, such as exercising, are often now performed indoors. Bacteria that colonize these indoor ecosystems are primarily derived from the human microbiome. The modes of human interaction with indoor surfaces and the physical conditions associated with each surface type determine the steady-state ecology of the microbial community. Bacterial assemblages associated with different surfaces in three athletic facilities, including floors, mats, benches, free weights, and elliptical handles, were sampled every other hour (8 am to 6 pm) for 2 days. Surface and equipment type had a stronger influence on bacterial community composition than the facility in which they were housed. Surfaces that were primarily in contact with human skin exhibited highly dynamic bacterial community composition and non-random co-occurrence patterns, suggesting that different host microbiomes—shaped by selective forces—were being deposited on these surfaces through time. However, bacterial assemblages found on the floors and mats changed less over time, and species co-occurrence patterns appeared random, suggesting more neutral community assembly. These longitudinal patterns highlight the dramatic turnover of microbial communities on surfaces in regular contact with human skin. By uncovering these longitudinal patterns, this study promotes a better understanding of microbe-human interactions within the built environment.
  • Article
    Auditory evoked potential audiometry in fish
    (Springer, 2013-01-18) Ladich, Friedrich ; Fay, Richard R.
    A recent survey lists more than 100 papers utilizing the auditory evoked potential (AEP) recording technique for studying hearing in fishes. More than 95 % of these AEP-studies were published after Kenyon et al. introduced a non-invasive electrophysiological approach in 1998 allowing rapid evaluation of hearing and repeated testing of animals. First, our review compares AEP hearing thresholds to behaviorally gained thresholds. Second, baseline hearing abilities are described and compared in 111 fish species out of 51 families. Following this, studies investigating the functional significance of various accessory hearing structures (Weberian ossicles, swim bladder, otic bladders) by eliminating these morphological structures in various ways are dealt with. Furthermore, studies on the ontogenetic development of hearing are summarized. The AEP-technique was frequently used to study the effects of high sound/noise levels on hearing in particular by measuring the temporary threshold shifts after exposure to various noise types (white noise, pure tones and anthropogenic noises). In addition, the hearing thresholds were determined in the presence of noise (white, ambient, ship noise) in several studies, a phenomenon termed masking. Various ecological (e.g., temperature, cave dwelling), genetic (e.g., albinism), methodical (e.g., ototoxic drugs, threshold criteria, speaker choice) and behavioral (e.g., dominance, reproductive status) factors potentially influencing hearing were investigated. Finally, the technique was successfully utilized to study acoustic communication by comparing hearing curves with sound spectra either under quiet conditions or in the presence of noise, by analyzing the temporal resolution ability of the auditory system and the detection of temporal, spectral and amplitude characteristics of conspecific vocalizations.
  • Article
    Augmin-dependent microtubule nucleation at microtubule walls in the spindle
    (Rockefeller University Press, 2013-07-01) Kamasaki, Tomoko ; O’Toole, Eileen ; Kita, Shigeo ; Osumi, Masako ; Usukura, Jiro ; McIntosh, J. Richard ; Goshima, Gohta
    The formation of a functional spindle requires microtubule (MT) nucleation from within the spindle, which depends on augmin. How augmin contributes to MT formation and organization is not known because augmin-dependent MTs have never been specifically visualized. In this paper, we identify augmin-dependent MTs and their connections to other MTs by electron tomography and 3D modeling. In metaphase spindles of human cells, the minus ends of MTs were located both around the centriole and in the body of the spindle. When augmin was knocked down, the latter population of MTs was significantly reduced. In control cells, we identified connections between the wall of one MT and the minus end of a neighboring MT. Interestingly, the connected MTs were nearly parallel, unlike other examples of end–wall connections between cytoskeletal polymers. Our observations support the concept of augmin-dependent MT nucleation at the walls of existing spindle MTs. Furthermore, they suggest a mechanism for maintaining polarized MT organization, even when noncentrosomal MT initiation is widespread.
  • Article
    Author correction: the solute carrier SLC9C1 is a Na(+)/H(+)-exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding
    (Nature Research, 2020-08-19) Windler, Florian ; Bönigk, Wolfgang ; Körschen, Heinz Gerd ; Grahn, Elena ; Strünker, Timo ; Seifert, Reinhard ; Kaupp, U. Benjamin
  • Article
    Axon-autonomous effects of the amyloid precursor protein intracellular domain (AICD) on kinase signaling and fast axonal transport
    (MDPI, 2023-10-04) Konig, Svenja ; Schmidt, Nadine ; Bechberger, Karin ; Morris, Sarah ; Priego, Mercedes ; Zaky, Hannah ; Song, Yuyu ; Pielage, Jan ; Brunholz, Silke ; Brady, Scott T. ; Kins, Stefan ; Morfini, Gerardo A.
    The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of kinase signaling pathways is well established in the context of full-length APP, little is known about intracellular effects of the AICD fragment, particularly within discrete neuronal compartments. Deficits in fast axonal transport (FAT) and axonopathy documented in AD-affected neurons prompted us to evaluate potential axon-autonomous effects of the AICD fragment for the first time. Vesicle motility assays using the isolated squid axoplasm preparation revealed inhibition of FAT by AICD. Biochemical experiments linked this effect to aberrant activation of selected axonal kinases and heightened phosphorylation of the anterograde motor protein conventional kinesin, consistent with precedents showing phosphorylation-dependent regulation of motors proteins powering FAT. Pharmacological inhibitors of these kinases alleviated the AICD inhibitory effect on FAT. Deletion experiments indicated this effect requires a sequence encompassing the NPTY motif in AICD and interacting axonal proteins containing a phosphotyrosine-binding domain. Collectively, these results provide a proof of principle for axon-specific effects of AICD, further suggesting a potential mechanistic framework linking alterations in APP processing, FAT deficits, and axonal pathology in AD.