Individual transcription factors modulate both the micromovement of chromatin and its long-range structure.

The control of eukaryotic gene expression is intimately connected to highly dynamic chromatin structures. Gene regulation relies on activator and repressor transcription factors (TFs) that induce local chromatin opening and closing. However, it is unclear how nucleus-wide chromatin organization responds dynamically to the activity of specific TFs. Here, we examined how two TFs with opposite effects on local chromatin accessibility modulate chromatin dynamics nucleus-wide. We combine high-resolution diffusion mapping and dense flow reconstruction and correlation in living cells to obtain an imaging-based, nanometer-scale analysis of local diffusion processes and long-range coordinated movements of both chromatin and TFs. We show that the expression of either an individual transcriptional activator (CDX2) or repressor (SIX6) with large numbers of binding sites increases chromatin mobility nucleus-wide, yet they induce opposite coherent chromatin motions at the micron scale. Hi-C analysis of higher-order chromatin structures shows that induction of the pioneer factor CDX2 leads both to changes in local chromatin interactions and the distribution of A and B compartments, thus relating the micromovement of chromatin with changes in compartmental structures. Given that inhibition of transcription initiation and elongation by RNA Pol II has a partial impact on the global chromatin dynamics induced by CDX2, we suggest that CDX2 overexpression alters chromatin structure dynamics both dependently and independently of transcription. Our biophysical analysis shows that sequence-specific TFs can influence chromatin structure on multiple architectural levels, arguing that local chromatin changes brought by TFs alter long-range chromatin mobility and its organization.

Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity.

How enhancers regulate their target genes in the context of 3D chromatin organization is extensively studied and models which do not require direct enhancer-promoter contact have recently emerged. Here, we use the activation of estrogen receptor-dependent enhancers in a breast cancer cell line to study enhancer-promoter communication at two loci. This allows high temporal resolution tracking of molecular events from hormone stimulation to efficient gene activation. We examine how both enhancer-promoter spatial proximity assayed by DNA fluorescence in situ hybridization, and contact frequencies resulting from chromatin in situ fragmentation and proximity ligation, change dynamically during enhancer-driven gene activation. These orthogonal methods produce seemingly paradoxical results: upon enhancer activation enhancer-promoter contact frequencies increase while spatial proximity decreases. We explore this apparent discrepancy using different estrogen receptor ligands and transcription inhibitors. Our data demonstrate that enhancer-promoter contact frequencies are transcription independent whereas altered enhancer-promoter proximity depends on transcription. Our results emphasize that the relationship between contact frequencies and physical distance in the nucleus, especially over short genomic distances, is not always a simple one.

Ultra-long-range interactions between active regulatory elements.

Contacts between enhancers and promoters are thought to relate to their ability to activate transcription. Investigating factors that contribute to such chromatin interactions is therefore important for understanding gene regulation. Here, we have determined contact frequencies between millions of pairs of cis-regulatory elements from chromosome conformation capture data sets and analyzed a collection of hundreds of DNA-binding factors for binding at regions of enriched contacts. This analysis revealed enriched contacts at sites bound by many factors associated with active transcription. We show that active regulatory elements, independent of cohesin and polycomb, interact with each other across distances of tens of megabases in vertebrate and invertebrate genomes and that interactions correlate and change with activity. However, these ultra-long-range interactions are not dependent on RNA polymerase II transcription or individual transcription cofactors. Using simulations, we show that a model of chromatin and multivalent binding factors can give rise to long-range interactions via bridging-induced clustering. We propose that long-range interactions between cis-regulatory elements are driven by at least three distinct processes: cohesin-mediated loop extrusion, polycomb contacts, and clustering of active regions.

Anion efflux mediates transduction in the hair cells of the zebrafish lateral line.

Hair cells are the principal sensory receptors of the vertebrate auditory system, where they transduce sounds through mechanically gated ion channels that permit cations to flow from the surrounding endolymph into the cells. The lateral line of zebrafish has served as a key model system for understanding hair cell physiology and development, often with the belief that these hair cells employ a similar transduction mechanism. In this study, we demonstrate that these hair cells are exposed to an unregulated external environment with cation concentrations that are too low to support transduction. Our results indicate that hair cell excitation is instead mediated by a substantially different mechanism involving the outward flow of anions. Further investigation of hair cell transduction in a diversity of sensory systems and species will likely yield deep insights into the physiology of these unique cells.

Septins mediate a microtubule-actin crosstalk that enables actin growth on microtubules.

Cellular morphogenesis and processes such as cell division and migration require the coordination of the microtubule and actin cytoskeletons. Microtubule-actin crosstalk is poorly understood and largely regarded as the capture and regulation of microtubules by actin. Septins are filamentous guanosine-5'-triphosphate (GTP) binding proteins, which comprise the fourth component of the cytoskeleton along microtubules, actin, and intermediate filaments. Here, we report that septins mediate microtubule-actin crosstalk by coupling actin polymerization to microtubule lattices. Superresolution and platinum replica electron microscopy (PREM) show that septins localize to overlapping microtubules and actin filaments in the growth cones of neurons and non-neuronal cells. We demonstrate that recombinant septin complexes directly crosslink microtubules and actin filaments into hybrid bundles. In vitro reconstitution assays reveal that microtubule-bound septins capture and align stable actin filaments with microtubules. Strikingly, septins enable the capture and polymerization of growing actin filaments on microtubule lattices. In neuronal growth cones, septins are required for the maintenance of the peripheral actin network that fans out from microtubules. These findings show that septins directly mediate microtubule interactions with actin filaments, and reveal a mechanism of microtubule-templated actin growth with broader significance for the self-organization of the cytoskeleton and cellular morphogenesis.

Microtubule-associated septin complexes modulate kinesin and dynein motility with differential specificities.

Long-range membrane traffic is guided by microtubule-associated proteins and posttranslational modifications, which collectively comprise a traffic code. The regulatory principles of this code and how it orchestrates the motility of kinesin and dynein motors are largely unknown. Septins are a large family of GTP-binding proteins, which assemble into complexes that associate with microtubules. Using single-molecule in vitro motility assays, we tested how the microtubule-associated SEPT2/6/7, SEPT2/6/7/9, and SEPT5/7/11 complexes affect the motilities of the constitutively active kinesins KIF5C and KIF1A and the dynein-dynactin-bicaudal D (DDB) motor complex. We found that microtubule-associated SEPT2/6/7 is a potent inhibitor of DDB and KIF5C, preventing mainly their association with microtubules. SEPT2/6/7 also inhibits KIF1A by obstructing stepping along microtubules. On SEPT2/6/7/9-coated microtubules, KIF1A inhibition is dampened by SEPT9, which alone enhances KIF1A, showing that individual septin subunits determine the regulatory properties of septin complexes. Strikingly, SEPT5/7/11 differs from SEPT2/6/7, in permitting the motility of KIF1A and immobilizing DDB to the microtubule lattice. In hippocampal neurons, filamentous SEPT5 colocalizes with somatodendritic microtubules that underlie Golgi membranes and lack SEPT6. Depletion of SEPT5 disrupts Golgi morphology and polarization of Golgi ribbons into the shaft of somato-proximal dendrites, which is consistent with the tethering of DDB to microtubules by SEPT5/7/11. Collectively, these results suggest that microtubule-associated complexes have differential specificities in the regulation of the motility and positioning of microtubule motors. We posit that septins are an integral part of the microtubule-based code that spatially controls membrane traffic.

Corollary discharge enables proprioception from lateral line sensory feedback.

Animals modulate sensory processing in concert with motor actions. Parallel copies of motor signals, called corollary discharge (CD), prepare the nervous system to process the mixture of externally and self-generated (reafferent) feedback that arises during locomotion. Commonly, CD in the peripheral nervous system cancels reafference to protect sensors and the central nervous system from being fatigued and overwhelmed by self-generated feedback. However, cancellation also limits the feedback that contributes to an animal's awareness of its body position and motion within the environment, the sense of proprioception. We propose that, rather than cancellation, CD to the fish lateral line organ restructures reafference to maximize proprioceptive information content. Fishes' undulatory body motions induce reafferent feedback that can encode the body's instantaneous configuration with respect to fluid flows. We combined experimental and computational analyses of swimming biomechanics and hair cell physiology to develop a neuromechanical model of how fish can track peak body curvature, a key signature of axial undulatory locomotion. Without CD, this computation would be challenged by sensory adaptation, typified by decaying sensitivity and phase distortions with respect to an input stimulus. We find that CD interacts synergistically with sensor polarization to sharpen sensitivity along sensors' preferred axes. The sharpening of sensitivity regulates spiking to a narrow interval coinciding with peak reafferent stimulation, which prevents adaptation and homogenizes the otherwise variable sensor output. Our integrative model reveals a vital role of CD for ensuring precise proprioceptive feedback during undulatory locomotion, which we term external proprioception.

A role for mitotic bookmarking of SOX2 in pluripotency and differentiation.

Mitotic bookmarking transcription factors remain bound to chromosomes during mitosis and were proposed to regulate phenotypic maintenance of stem and progenitor cells at the mitosis-to-G1 (M-G1) transition. However, mitotic bookmarking remains largely unexplored in most stem cell types, and its functional relevance for cell fate decisions remains unclear. Here we screened for mitotic chromosome binding within the pluripotency network of embryonic stem (ES) cells and show that SOX2 and OCT4 remain bound to mitotic chromatin through their respective DNA-binding domains. Dynamic characterization using photobleaching-based methods and single-molecule imaging revealed quantitatively similar specific DNA interactions, but different nonspecific DNA interactions, of SOX2 and OCT4 with mitotic chromatin. Using ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) to assess the genome-wide distribution of SOX2 on mitotic chromatin, we demonstrate the bookmarking activity of SOX2 on a small set of genes. Finally, we investigated the function of SOX2 mitotic bookmarking in cell fate decisions and show that its absence at the M-G1 transition impairs pluripotency maintenance and abrogates its ability to induce neuroectodermal differentiation but does not affect reprogramming efficiency toward induced pluripotent stem cells. Our study demonstrates the mitotic bookmarking property of SOX2 and reveals its functional importance in pluripotency maintenance and ES cell differentiation.

Systematic conservation planning for Antarctic research stations.

The small ice-free areas of Antarctica are essential locations for both biodiversity and scientific research but are subject to considerable and expanding human impacts, resulting primarily from station-based research and support activities, and local tourism. Awareness by operators of the need to conserve natural values in and around station and visitor site footprints exists, but the cumulative nature of impacts often results in reactive rather than proactive management. With human activity spread across many isolated pockets of ice-free ground, the pathway to the greatest reduction of human impacts within this natural reserve is through better management of these areas, which are impacted the most. Using a case study of Australia's Casey Station, we found significant natural values persist within the immediate proximity (<10 m) of long-term station infrastructure, but encroachment by physical disturbance results in ongoing pressures. Active planning to better conserve such values would provide a direct opportunity to enhance protection of Antarctica's environment. Here we introduce an approach to systematic conservation planning, tailored to Antarctic research stations, to help managers improve the conservation of values surrounding their activity locations. Use of this approach provides a potential mechanism to balance the need for scientific access to the continent with international obligations to protect its environment. It may also facilitate the development of subordinate conservation tools, including management plans and natural capital accounting. By proactively minimising and containing their station footprints, national programs can also independently demonstrate their commitment to protecting Antarctica's environment.

A sensitive and affordable multiplex RT-qPCR assay for SARS-CoV-2 detection.

With the ongoing COVID-19 (Coronavirus Disease 2019) pandemic, caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), there is a need for sensitive, specific, and affordable diagnostic tests to identify infected individuals, not all of whom are symptomatic. The most sensitive test involves the detection of viral RNA using RT-qPCR (quantitative reverse transcription PCR), with many commercial kits now available for this purpose. However, these are expensive, and supply of such kits in sufficient numbers cannot always be guaranteed. We therefore developed a multiplex assay using well-established SARS-CoV-2 targets alongside a human cellular control (RPP30) and a viral spike-in control (Phocine Herpes Virus 1 [PhHV-1]), which monitor sample quality and nucleic acid extraction efficiency, respectively. Here, we establish that this test performs as well as widely used commercial assays, but at substantially reduced cost. Furthermore, we demonstrate >1,000-fold variability in material routinely collected by combined nose and throat swabbing and establish a statistically significant correlation between the detected level of human and SARS-CoV-2 nucleic acids. The inclusion of the human control probe in our assay therefore provides a quantitative measure of sample quality that could help reduce false-negative rates. We demonstrate the feasibility of establishing a robust RT-qPCR assay at approximately 10% of the cost of equivalent commercial assays, which could benefit low-resource environments and make high-volume testing affordable.

Proteomic profiling of the oncogenic septin 9 reveals isoform-specific interactions in breast cancer cells.

Septins are a family of multimeric GTP-binding proteins, which are abnormally expressed in cancer. Septin 9 (SEPT9) is an essential and ubiquitously expressed septin with multiple isoforms, which have differential expression patterns and effects in breast cancer cells. It is unknown, however, if SEPT9 isoforms associate with different molecular networks and functions. Here, we performed a proteomic screen in MCF-7 breast cancer cells to identify the interactome of GFP-SEPT9 isoforms 1, 4 and 5, which vary significantly in their N-terminal extensions. While all three isoforms associated with SEPT2 and SEPT7, the truncated SEPT9_i4 and SEPT9_i5 interacted with septins of the SEPT6 group more promiscuously than SEPT9_i1, which bound predominately SEPT8. Spatial mapping and functional clustering of non-septin partners showed isoform-specific differences in interactions with proteins of distinct subcellular organelles (e.g., nuclei, centrosomes, cilia) and functions such as cell signalling and ubiquitination. The interactome of the full length SEPT9_i1 was more enriched in cytoskeletal regulators, while the truncated SEPT9_i4 and SEPT9_i5 exhibited preferential and isoform-specific interactions with nuclear, signalling, and ubiquitinating proteins. These data provide evidence for isoform-specific interactions, which arise from truncations in the N-terminal extensions of SEPT9, and point to novel roles in the pathogenesis of breast cancer.

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes.

PURPOSE: Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS). METHODS: We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months-21 years). RESULTS: With a median follow-up of 26 months (range 7 months-9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III-IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%. CONCLUSION: This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04232085.

Pleiotropic roles of tankyrase/PARP proteins in the establishment and maintenance of human naïve pluripotency.

Tankyrase 1 (TNKS1; PARP-5a) and Tankyrase 2 (TNKS2; PARP-5b) are poly-ADP-ribosyl-polymerase (PARP)-domain-containing proteins that regulate the activities of a wide repertoire of target proteins via post-translational addition of poly-ADP-ribose polymers (PARylation). Although tankyrases were first identified as regulators of human telomere elongation, important and expansive roles of tankyrase activity have recently emerged in the development and maintenance of stem cell states. Herein, we summarize the current state of knowledge of the various tankyrase-mediated activities that may promote human naïve and 'extended' pluripotency'. We review the putative role of tankyrase and PARP inhibition in trophectoderm specification, telomere elongation, DNA repair and chromosomal segregation, metabolism, and PTEN-mediated apoptosis. Importantly, tankyrases possess PARP-independent activities that include regulation of MDC1-associated DNA repair by homologous recombination (HR) and autophagy/pexophagy, which is an essential mechanism of protein synthesis in the preimplantation embryo. Additionally, tankyrases auto-regulate themselves via auto-PARylation which augments their cellular protein levels and potentiates their non-PARP tankyrase functions. We propose that these non-PARP-related activities of tankyrase proteins may further independently affect both naïve and extended pluripotency via mechanisms that remain undetermined. We broadly outline a hypothetical framework for how inclusion of a tankyrase/PARP inhibitor in small molecule cocktails may stabilize and potentiate naïve and extended pluripotency via pleiotropic routes and mechanisms.

Prolonged water immersion alters resistance to sliding of aesthetic orthodontic coated wires.

OBJECTIVE: The objective of this study was to compare the resistance to sliding of aesthetic orthodontic coated wires after prolonged water immersion for up to 4 weeks. SETTING AND SAMPLE POPULATION: An in vitro study of commercially available orthodontic appliances. MATERIALS AND METHODS: Aesthetic coated stainless-steel wires (Parylene-coated, epoxy-coated and Teflon-coated) (0.019" × 0.025") and an uncoated control were immersed in distilled-deionized water for zero, two or four weeks at 37°C and then were subjected to resistance-to-sliding tests through a three-bracket system of sapphire ceramic brackets (0.022" × 0.028" slot) and clear-coloured elastic ligatures at a contact angle of 0° or 3°. Maximal and average resistance to sliding was analysed by a three-way analysis of variance, two general linear models and a post hoc Tukey's honest significant difference test. RESULTS: Water immersion time, contact angle, wire group and their interactions had statistically significant effects on the resistance to sliding of tested orthodontic wires. Various coated wires had distinct timely changes in the maximal and average resistance to sliding after water immersion for 2 to 4 weeks. When compared to the uncoated control in most of the experimental conditions, epoxy-coated wires had lower or non-significant differences in resistance to sliding, while Parylene-coated wire had higher resistances. CONCLUSIONS: Prolonged water immersion for weeks alters the resistance to sliding of aesthetic orthodontic wires coated with Parylene, epoxy or Teflon. Based on their resistance to sliding, different designs in orthodontic biomechanics should be considered for the different aesthetic orthodontic coated wires.

Spatial control of membrane traffic in neuronal dendrites.

Neuronal dendrites are highly branched and specialized compartments with distinct structures and secretory organelles (e.g., spines, Golgi outposts), and a unique cytoskeletal organization that includes microtubules of mixed polarity. Dendritic membranes are enriched with proteins, which specialize in the formation and function of the post-synaptic membrane of the neuronal synapse. How these proteins partition preferentially in dendrites, and how they traffic in a manner that is spatiotemporally accurate and regulated by synaptic activity are long-standing questions of neuronal cell biology. Recent studies have shed new insights into the spatial control of dendritic membrane traffic, revealing new classes of proteins (e.g., septins) and cytoskeleton-based mechanisms with dendrite-specific functions. Here, we review these advances by revisiting the fundamental mechanisms that control membrane traffic at the levels of protein sorting and motor-driven transport on microtubules and actin filaments. Overall, dendrites possess unique mechanisms for the spatial control of membrane traffic, which might have specialized and co-evolved with their highly arborized morphology.

Spatial effects - site-specific regulation of actin and microtubule organization by septin GTPases.

The actin and microtubule cytoskeletons comprise a variety of networks with distinct architectures, dynamics and protein composition. A fundamental question in eukaryotic cell biology is how these networks are spatially and temporally controlled, so they are positioned in the right intracellular places at the right time. While significant progress has been made in understanding the self-assembly of actin and microtubule networks, less is known about how they are patterned and regulated in a site-specific manner. In mammalian systems, septins are a large family of GTP-binding proteins that multimerize into higher-order structures, which associate with distinct subsets of actin filaments and microtubules, as well as membranes of specific curvature and lipid composition. Recent studies have shed more light on how septins interact with actin and microtubules, and raised the possibility that the cytoskeletal topology of septins is determined by their membrane specificity. Importantly, new functions have emerged for septins regarding the generation, maintenance and positioning of cytoskeletal networks with distinct organization and biochemical makeup. This Review presents new and past findings, and discusses septins as a unique regulatory module that instructs the local differentiation and positioning of distinct actin and microtubule networks.

Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions.

SOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self-renewal and differentiation. How temporal fluctuations in their expression levels bias lineage commitment is unknown. Here, we generated knock-in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cells towards both neuroectodermal and mesendodermal fates in undirected differentiation. Using ATAC-seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation-associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration-dependent priming of differentiation-associated enhancers.

Clinical Reliability of point-of-care tests to support community based acute ambulatory care.

OBJECTIVE: To ensure clinicians can rely on point-of-care testing results, we assessed agreement between point-of-care tests for creatinine, urea, sodium, potassium, calcium, Hb, INR, CRP and subsequent corresponding laboratory tests. PARTICIPANTS: Community-dwelling adults referred to a community-based acute ambulatory care unit. INTERVENTIONS: The Abbott i-STATTM (Hb, clinical chemistry, INR) and the AfinionTM Analyser (CRP) and corresponding laboratory analyses. OUTCOMES: Agreement (Bland-Altman) and bias (Passing-Bablok regression). RESULTS: Among 462 adults we found an absolute mean difference between point-of-care and central laboratory analyses of 6.4g/L (95%LOA -7.9 to +20.6) for haemoglobin, -0.5mmol/L (95%LOA -4.5 to +3.5) for sodium, 0.2mmol/L (95%LOA -0.6 to +0.9) for potassium, 0.0mmol/L (95%LOA -0.3 to +0.3) for calcium, 9.0 µmol/L (95%LOA -18.5 to +36.4) for creatinine, 0.0mmol/L (95%LOA -2.7 to +2.6) for urea, -0.2 (95%LOA -2.4 to +2.0) for INR, -5.0 mg/L (95%LOA -24.4 to +14.4) for CRP. CONCLUSIONS: There was acceptable agreement and bias for these analytes, except for haemoglobin and creatinine.

Efferent modulation of spontaneous lateral line activity during and after zebrafish motor commands.

Accurate sensory processing during movement requires the animal to distinguish between external (exafferent) and self-generated (reafferent) stimuli to maintain sensitivity to biologically relevant cues. The lateral line system in fishes is a mechanosensory organ that experiences reafferent sensory feedback, via detection of fluid motion relative to the body generated during behaviors such as swimming. For the first time in larval zebrafish (Danio rerio), we employed simultaneous recordings of lateral line and motor activity to reveal the activity of afferent neurons arising from endogenous feedback from hindbrain efferent neurons during locomotion. Frequency of spontaneous spiking in posterior lateral line afferent neurons decreased during motor activity and was absent for more than half of swimming trials. Targeted photoablation of efferent neurons abolished the afferent inhibition that was correlated to swimming, indicating that inhibitory efferent neurons are necessary for modulating lateral line sensitivity during locomotion. We monitored calcium activity with Tg(elav13:GCaMP6s) fish and found synchronous activity between putative cholinergic efferent neurons and motor neurons. We examined correlates of motor activity to determine which may best predict the attenuation of afferent activity and therefore what components of the motor signal are translated through the corollary discharge. Swim duration was most strongly correlated to the change in afferent spike frequency. Attenuated spike frequency persisted past the end of the fictive swim bout, suggesting that corollary discharge also affects the glide phase of burst and glide locomotion. The duration of the glide in which spike frequency was attenuated increased with swim duration but decreased with motor frequency. Our results detail a neuromodulatory mechanism in larval zebrafish that adaptively filters self-generated flow stimuli during both the active and passive phases of locomotion.NEW & NOTEWORTHY For the first time in vivo, we quantify the endogenous effect of efferent activity on afferent gain control in a vertebrate hair cell system during and after locomotion. We believe that this pervasive effect has been underestimated when afferent activity of octavolateralis systems is characterized in the current literature. We further identify a refractory period out of phase with efferent control and place this gain mechanism in the context of gliding behavior of freely moving animals.