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Most of us live blissfully unaware of the orchestrated function that our internal organs conduct. When this peace is interrupted, it is often by routine sensations of hunger and urge. However, for >20% of the global population, chronic visceral pain is an unpleasant and often excruciating reminder of the existence of our internal organs. In many cases, there is no obvious underlying pathological cause of the pain. Accordingly, chronic visceral pain is debilitating, reduces the quality of life of sufferers, and has large concomitant socioeconomic costs. In this review, we highlight key mechanisms underlying chronic abdominal and pelvic pain associated with functional and inflammatory disorders of the gastrointestinal and urinary tracts. This includes how the colon and bladder are innervated by specialized subclasses of spinal afferents, how these afferents become sensitized in highly dynamic signaling environments, and the subsequent development of neuroplasticity within visceral pain pathways. We also highlight key contributing factors, including alterations in commensal bacteria, altered mucosal permeability, epithelial interactions with afferent nerves, alterations in immune or stress responses, and cross talk between these two adjacent organs. [ABSTRACT FROM AUTHOR]

Although perhaps best known for their use in developmental studies, over the last couple of decades, zebrafish have become increasingly popular model organisms for investigating auditory system function and disease. Like mammals, zebrafish possess inner ear mechanosensory hair cells required for hearing, as well as superficial hair cells of the lateral line sensory system, which mediate detection of directional water flow. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of hair cell biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired hair cell dysfunction. Here, we provide an overview of this literature, highlighting some of the particular advantages of using zebrafish to investigate hearing and hearing loss. [ABSTRACT FROM AUTHOR]

Hair cells transmit mechanical information by converting deflection of the hair bundle into synaptic release of glutamate. We have investigated this process in the lateral line of larval zebrafish (male and female) to understand how stimuli are encoded within a neuromast. Using multiphoton microscopy in vivo, we imaged synaptic release of glutamate using the reporter iGluSnFR as well as deflections of the cupula. We found that the neuromast is composed of a functionally diverse population of hair cells. Half the hair cells signaled cupula motion in both directions from rest, either by increasing glutamate release in response to a deflection in the positive direction or by reducing release in the negative direction. The relationship between cupula deflection and glutamate release demonstrated maximum sensitivity at displacements of just--40 nm in the positive direction. The remaining hair cells only signaled motion in one direction and were less sensitive, extending the operating range of the neuromast beyond 1 ju.ni. Adaptation of the synaptic output was also heterogeneous, with some hair cells generating sustained glutamate release in response to a steady deflection of the cupula and others generating transient outputs. Finally, a distinct signal encoded a return of the cupula to rest: a large and transient burst of glutamate release from hair cells unresponsive to the initial stimulus. A population of hair cells with these different sensitivities, operating ranges, and adaptive properties will allow the neuromast to encode weak stimuli while maintaining the dynamic range to signal the amplitude and duration of stronger deflections. [ABSTRACT FROM AUTHOR]

Esophageal diseases are highly prevalent and carry significant socioeconomic burden. Despite the apparently simple function of the esophagus, we still struggle to better understand its physiology and pathophysiology. The assessment of large data sets and application of multiscale mathematical organ models have gained attention as part of the Physiome Project. This has long been recognized in cardiology but has only recently gained attention for the gastrointestinal(GI) tract. The term "esophagiome" implies a holistic assessment of esophageal function, from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. These anatomical, mechanical, and physiological models underlie the development of a "virtual esophagus" modeling framework to characterize and analyze function and disease. Functional models incorporate anatomical details with sensory–motor responses, especially related to biomechanical functions such as bolus transport. Our review builds on previous reviews and focuses on assessment of detailed anatomical and geometric data using advanced imaging technology for evaluation of gastro‐esophageal reflux disease (GERD), and on esophageal mechanophysiology assessed using technologies that distend the esophagus. Integration of mechanics‐ and physiology‐based analysis is a useful characteristic of the esophagiome. Experimental data on pressures and geometric characteristics are useful for the validation of mathematical and computer models of the esophagus that may provide predictions of novel endoscopic, surgical, and pharmaceutical treatment options. The physiology and pathophysiology of the esophagus is still not completely understood. This has led to the esophagiome project, a holistic assessment of esophageal function, from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. The focus of this review on the esophagiome is on the assessment of detailed anatomical and geometric data using advanced imaging technology for evaluation of gastro‐esophageal reflux disease, and on esophageal mechanophysiology assessed using technologies that distend the esophagus. [ABSTRACT FROM AUTHOR]

Many internal organs change volume periodically. For example, the stomach accommodates ingested food and drink, the bladder stores urine, the heart fills with blood, and the lungs expand with every breath. Specialized peripheral sensory neurons function as mechanoreceptors that detect tissue stretch to infer changes in organ volume and then relay this information to the brain. Central neural circuits process this information and evoke perceptions (satiety, nausea), control physiology (breathing, heart rate), and impact behavior (feeding, micturition). Yet, basic questions remain about how neurons sense organ distension and whether common sensory motifs are involved across organs. Here, we review candidate mechanosensory receptors, cell types, and neural circuits, focusing on the stomach, bladder, and airways. Understanding mechanisms of organ stretch sensation may provide new ways to treat autonomic dysfunction. Highlights Sensory neurons detect stretch of bladder, stomach, and airways to inform on organ volume and enable appropriate physiological and behavioral responses. Piezo2 mediates airway stretch sensation and the Hering–Breuer inspiratory reflex. Stomach stretch is sensed by IGLE terminals between layers of stomach muscle. Primary mechanoreceptors that underlie afferent nerve responses to bladder and stomach stretch sensation are unknown. [ABSTRACT FROM AUTHOR]

Highlights • Adult zebrafish are piscivorous predators of conspecific larvae. • Prey capture by adult zebrafish is guided primarily by vision. • Olfactory and mechanosensory cues are dispensable for piscivory by zebrafish. • Zebrafish employ an active predation strategy to hunt larval fish. Abstract The sensory modalities used by predatory fish to detect and capture prey are a key dimension of their foraging strategy. Determining the sensory cues that guide predation can also further conservation efforts under environmental change, and address the welfare of research animals. Here, we experimentally manipulated the sensory modalities used by adult zebrafish (Danio rerio) when foraging for larval conspecifics in captivity. We used minimally invasive techniques to test the consequences of eliminating visual, olfactory, and mechanosensory cues for predator behavior and success. Our results indicate that zebrafish require visual cues, but not olfactory or mechanosensory input. Reducing the visual contrast between prey and their surroundings decreased capture rates, suggesting that contrast underlies visual foraging. Video recordings of zebrafish during foraging indicate that they actively hunt larval fish, rather than employing a sit-and-wait approach. Together, our findings indicate adult zebrafish rely on visual cues to guide an active predation strategy. [ABSTRACT FROM AUTHOR]

Male oyster toadfish (Opsanus tau) acoustically attract females to nesting sites using a boatwhistle call. The rapid speed of sound underwater combined with the close proximity of the otolithic organs makes inner ear interaural time differences an unlikely mechanism to localize sound. To determine the role that the mechanosensory lateral line may play in sound localization, microwire electrodes were bilaterally implanted into the anterior lateral line nerve to record neural responses to vibrational stimuli. Highest spike rates and strongest phase-locking occurred at distances close to the fish and decreased as the stimulus was moved further from the fish. Bilateral anterior lateral line neuromasts displayed differential directional sensitivity to incoming vibrational stimuli, which suggests the potential for the lateral line to be used for sound localization in the near field. The present study also demonstrates that the spatially separated neuromasts of the toadfish may provide sufficient time delays between sensory organs for determining sound localization cues. Multimodal sensory input processing through both the inner ear (far field) and lateral line (near field) may allow for effective sound localization in fish. [ABSTRACT FROM AUTHOR]

Habituation is a ubiquitous form of non-associative learning observed as a decrement in responding to repeated stimulation that cannot be explained by sensory adaptation or motor fatigue. One of the defining characteristics of habituation is its sensitivity to the rate at which training stimuli are presented--animals habituate faster in response to more rapid stimulation. The molecular mechanisms underlying this interstimulus interval (ISI)-dependent characteristic of habituation remain unknown. In this article, we use behavioural neurogenetic and bioinformatic analyses in the nematode Caenorhabiditis elegans to identify the first molecules that modulate habituation in an ISI-dependent manner. We show that the Caenorhabditis elegans orthologues of Ca2+ calmodulin-dependent kinases CaMK1/4, CMK-1 and O-linked N-acetylglucosamine (O-GlcNAc) transferase, OGT-1, both function in primary sensory neurons to inhibit habituation at short ISIs and promote it at long ISIs. In addition, both cmk-1 and ogt-1 mutants display a raremechanosensory hyper-responsive phenotype (i.e. larger mechanosensory responses than wild-type).Overall, our work identifies two conserved genes that function in sensory neurons to modulate habituation in an ISI-dependent manner, providing the first insights into the molecular mechanisms underlying the universally observed phenomenon that habituation has different properties when stimuli are delivered at different rates. [ABSTRACT FROM AUTHOR]

The emerald jewel wasp (Ampulex compressa) is renowned for its ability to zombify the American cockroach (Periplaneta americana) with a sting to the brain. When the venom takes effect, the cockroach becomes passive and can be led by its antenna into a hole, where the wasp deposits an egg and then seals the exit with debris. The cockroach has the ability to walk, run, or fly if properly stimulated, but it does not try to escape as it is slowly eaten alive by the developing wasp larva. Although the composition and effects of the wasp's venom have been investigated, no studies have detailed how cockroaches might prevent this grim fate. Here it is shown that many cockroaches deter wasps with a vigorous defense. Successful cockroaches elevated their bodies, bringing their neck out of reach, and kicked at the wasp with their spiny hind legs, often striking the wasp's head multiple times. Failing this, the elevated, "on-guard" position allowed cockroaches to detect and evade the wasp's lunging attack. If grasped, the cockroaches parried the stinger with their legs, used a "stiff-arm" defense to hold back the stinger, and could stab at, and dislodge, the wasp with tibial spines. Lastly, cockroaches bit at the abdomen of wasps delivering the brain sting. An aggressive defense from the outset was most successful. Thus, for a cockroach not to become a zombie, the best strategy is: be vigilant, protect your throat, and strike repeatedly at the head of the attacker. [ABSTRACT FROM AUTHOR]

We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis.

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the potential of FM 1-43 by using it to identify novel PIEZO2-expressing urethral neurons that are engaged by urination. These data reveal that FM 1-43 is a functional probe for mechanosensitivity via PIEZO2 activation in vivo and will facilitate the characterization of known and novel mechanosensory processes in multiple organ systems. • FM 1-43 is a fluorescent dye that labels mouse sensory neurons in vivo • Sensory neuron FM 1-43 labeling requires the activity of the mechanosensor PIEZO2 • FM 1-43 reveals a PIEZO2-dependent urethral neuron that is engaged during urination • This dye is a useful tool for identifying when and where PIEZO2 is active in vivo Mechanosensory processes are critical for the function of many organ systems. Villarino et al. find that the fluorescent dye FM 1-43 specifically labels the activity of the mechanosensitive ion channel PIEZO2 in mouse sensory neurons in vivo. This tool enables characterization of neuronal processes that rely on this important mechanosensor. [ABSTRACT FROM AUTHOR]

How the Venus flytrap (Dionaea muscipula) evolved the remarkable ability to sense, capture, and digest animal prey for nutrients has long puzzled the scientific community. 1 Recent genome and transcriptome sequencing studies have provided clues to the genes thought to play a role in these tasks. 2,3,4,5 However, proving a causal link between these and any aspect of the plant's hunting behavior has been challenging due to the genetic intractability of this non-model organism. Here, we use CRISPR-Cas9 methods to generate targeted modifications in the Venus flytrap genome. The plant detects prey using touch-sensitive trigger hairs located on its bilobed leaves. 6 Upon bending, these hairs convert mechanical touch signals into changes in the membrane potential of sensory cells, leading to rapid closure of the leaf lobes to ensnare the animal. 7 Here, we generate mutations in trigger-hair-expressed MscS-like (MSL)-family mechanosensitive ion channel genes FLYCATCHER1 (FLYC1) and FLYCATCHER2 (FLYC2) 5 and find that double-mutant plants have a reduced leaf-closing response to mechanical ultrasound stimulation. While we cannot exclude off-target effects of the CRISPR-Cas9 system, our genetic analysis is consistent with these and other functionally redundant mechanosensitive ion channels acting together to generate the sensory system necessary for prey detection. [Display omitted] • The CRISPR-Cas9 system can be used to genetically modify Venus flytrap plants • Loss of the mechanosensitive ion channel FLYC1 does not impair leaf function • flyc1 flyc2 double mutants have a reduced response to mechanical stimulation Ion channel genes FLYC1 and FLYC2 are expressed in touch-sensing structures of the carnivorous Venus flytrap plant. Procko et al. show that when these genes are mutated, Venus flytrap leaves have a reduced response to mechanical ultrasound stimulation. Thus, these channels may function redundantly with others for sensing mechanical stimuli. [ABSTRACT FROM AUTHOR]

The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention. [Display omitted] • Five genetic subtypes of DRG sensory afferents innervate the distal colon • These subtypes have diverse ending morphologies in the colon • The responses of four subtypes to colon distension have distinct physiologic properties • One subtype (Bmpr1b+) is hyper-reactive to colonic distension during inflammation Distinct subtypes of colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space. The highest threshold subtype is hyper-reactive to colonic distension during inflammation. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal. [Display omitted] • Individuals with PIEZO2 syndrome present impaired bowel sensation and GI dysfunction • Piezo2 in DRG neurons plays an important role in regulating gut motility • Lack of Piezo2 from sensory neurons accelerates gastric emptying and intestinal transit • DRG neurons detect colon distension via Piezo2 Piezo2 in dorsal root ganglia neurons is required to sense gut content and slow down food transit rates in the stomach, small intestine, and colon. [ABSTRACT FROM AUTHOR]

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders. [Display omitted] • Prox2/Runx3 vagal sensory neurons form intraganglionic laminar endings in the esophagus • Prox2/Runx3 vagal sensory neurons function as mechanoreceptors • Prox2/Runx3 vagal sensory neurons are required for swallowing in freely behaving mice The vagal sensory neurons that monitor esophageal stretch and distension belong to the MM2 and MM8 subtypes of Prox2/Runx3 neurons. These two subtypes are key for swallowing in vivo , as their ablation causes severe esophageal dysmotility. Knowledge about their molecular makeup might help treat esophageal disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to immunolocalise type VI collagen and perlecan and determine their interactive properties in the intervertebral disc (IVD). Confocal laser scanning microscopy co-localised perlecan with type VI collagen as pericellular components of IVD cells and translamellar cross-bridges in ovine and murine IVDs. These cross-bridges were significantly less abundant in the heparin sulphate deficient Hspg2 exon 3 null mouse IVD than in wild type. This association of type VI collagen with elastic components provides clues as to its roles in conveying elastic recoil properties to annular tissues. Perlecan and type VI collagen were highly interactive in plasmon resonance studies. Pericellular colocalisation of perlecan and type VI collagen provides matrix stabilisation and cell-matrix communication which allows IVD cells to perceive and respond to perturbations in their biomechanical microenvironment. Perlecan, at the cell surface, provides an adhesive interface between the cell and its surrounding extracellular matrix. Elastic microfibrillar structures regulate tensional connective tissue development and function. The 2010 Global Burden of Disease study examined 291 disorders and identified disc degeneration and associated low back pain as the leading global musculoskeletal disorder emphasising its massive socioeconomic impact and the need for more effective treatment strategies. A greater understanding of how the IVD achieves its unique biomechanical functional properties is of great importance in the development of such therapeutic measures.

Osteocytes are involved in mechanosensation and mechanotransduction in bone and hence, are key to bone adaptation in response to development, ageing and disease. Thus, detailed knowledge of the three-dimensional (3D) structure of the osteocyte network (ON) and the surrounding lacuno-canalicular network (LCN) is essential. Enhanced understanding of the ON&LCN will contribute to a better understanding of bone mechanics on cellular and sub-cellular scales, for instance through improved computational models of bone mechanotransduction. Until now, the location of the ON within the hard bone matrix and the sub-µm dimensions of the ON&LCN have posed significant challenges for 3D imaging. This review identifies relevant microstructural phenotypes of the ON&LCN in health and disease and summarises how light microscopy, electron microscopy and X-ray imaging techniques have been used in studies of osteocyte anatomy, pathology and mechanobiology to date. In this review, we assess the requirements for ON&LCN imaging and examine the state of the art in the fields of imaging and computational modelling as well as recent advances in high-resolution 3D imaging. Suggestions for future investigations using volume electron microscopy are indicated and we present new data on the ON&LCN using serial block-face scanning electron microscopy. A correlative approach using these high-resolution 3D imaging techniques in conjunction with in silico modelling in bone mechanobiology will increase understanding of osteocyte function and, ultimately, lead to improved pathways for diagnosis and treatment of bone diseases such as osteoporosis.

The calcium ion (Ca2+) is a diverse secondary messenger with a near-ubiquitous role in a vast array of cellular processes. Cilia are present on nearly every cell type in either a motile or non-motile form; motile cilia generate fluid flow needed for a variety of biological processes, such as left–right body patterning during development, while non-motile cilia serve as the signaling powerhouses of the cell, with vital singling receptors localized to their ciliary membranes. Much of the research currently available on Ca2+-dependent cellular actions and primary cilia are tissue-specific processes. However, basic stimuli-sensing pathways, such as mechanosensation, chemosensation, and electrical sensation (electrosensation), are complex processes entangled in many intersecting pathways; an overview of proposed functions involving cilia and Ca2+ interplay will be briefly summarized here. Next, we will focus on summarizing the evidence for their interactions in basic cellular activities, including the cell cycle, cell polarity and migration, neuronal pattering, glucose-mediated insulin secretion, biliary regulation, and bone formation. Literature investigating the role of cilia and Ca2+-dependent processes at a single-cellular level appears to be scarce, though overlapping signaling pathways imply that cilia and Ca2+ interact with each other on this level in widespread and varied ways on a perpetual basis. Vastly different cellular functions across many different cell types depend on context-specific Ca2+ and cilia interactions to trigger the correct physiological responses, and abnormalities in these interactions, whether at the tissue or the single-cell level, can result in diseases known as ciliopathies; due to their clinical relevance, pathological alterations of cilia function and Ca2+ signaling will also be briefly touched upon throughout this review.

Mechanotransduction is the interpretation of physical cues by cells through mechanosensation mechanisms that elegantly translate mechanical stimuli into biochemical signaling pathways. While mechanical stress and their resulting cellular responses occur in normal physiologic contexts, there are a variety of cancer-associated physical cues present in the tumor microenvironment that are pathological in breast cancer. Mechanistic in vitro data and in vivo evidence currently support three mechanical stressors as mechanical modifiers in breast cancer that will be the focus of this review: stiffness, interstitial fluid pressure, and solid stress. Increases in stiffness, interstitial fluid pressure, and solid stress are thought to promote malignant phenotypes in normal breast epithelial cells, as well as exacerbate malignant phenotypes in breast cancer cells.

Cdc14 is an evolutionarily conserved serine/threonine phosphatase. Originally identified in Saccharomyces cerevisiae as a cell cycle regulator, its role in other eukaryotic organisms remains unclear. In Drosophila melanogaster, Cdc14 is encoded by a single gene, thus facilitating its study. We found that Cdc14 expression is highest in the testis of adult flies and that cdc14 null flies are viable. cdc14 null female and male flies do not display altered fertility. cdc14 null males, however, exhibit decreased sperm competitiveness. Previous studies have shown that Cdc14 plays a role in ciliogenesis during zebrafish development. In Drosophila, sensory neurons are ciliated. We found that the Drosophila cdc14 null mutants have defects in chemosensation and mechanosensation as indicated by decreased avoidance of repellant substances and decreased response to touch. In addition, we show that cdc14 null mutants have defects in lipid metabolism and resistance to starvation. These studies highlight the diversity of Cdc14 function in eukaryotes despite its structural conservation.

Diseases affecting the glomeruli of the kidney, the renal filtration units, are a leading cause of chronic kidney disease and end-stage renal failure. Despite recent advances in the understanding of glomerular biology, treatment of these disorders has remained extraordinarily challenging in many cases. The use of experimental models has proven invaluable to study renal, and in particular, glomerular biology and disease. Over the past 15 years, studies identified different and very distinct pathogenic mechanisms that result in damage, loss of glomerular visceral epithelial cells (podocytes) and progressive renal disease. However, animal studies and, in particular, mouse studies are often protracted and cumbersome due to the long reproductive cycle and high keeping costs. Transgenic and heterologous expression models have been speeded-up by novel gene editing techniques, yet they still take months. In addition, given the complex cellular biology of the filtration barrier, certain questions may not be directly addressed using mouse models due to the limited accessibility of podocytes for analysis and imaging. In this review, we will describe alternative models to study podocyte biology experimentally. We specifically discuss current podocyte cell culture models, their role in experimental strategies to analyze pathophysiologic mechanisms as well as limitations with regard to transferability of results. We introduce current models in Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio that allow for analysis of protein interactions, and principle signaling pathways in functional biological structures, and enable high-throughput transgenic expression or compound screens in multicellular organisms.

The hair cell mechanotransduction (MET) channel complex is essential for hearing, yet it’s molecular identity and structure remain elusive. The transmembrane channel–like 1 (TMC1) protein localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors the Beethoven mutation, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextrans, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.

A quantitative understanding of how sensory signals are transformed into motor outputs places useful constraints on brain function and helps to reveal the brain’s underlying computations. We investigate how the nematode Caenorhabditis elegans responds to time-varying mechanosensory signals using a high-throughput optogenetic assay and automated behavior quantification. We find that the behavioral response is tuned to temporal properties of mechanosensory signals, such as their integral and derivative, that extend over many seconds. Mechanosensory signals, even in the same neurons, can be tailored to elicit different behavioral responses. Moreover, we find that the animal’s response also depends on its behavioral context. Most dramatically, the animal ignores all tested mechanosensory stimuli during turns. Finally, we present a linear-nonlinear model that predicts the animal’s behavioral response to stimulus.

The upper gastrointestinal tract plays an important role in sensing the arrival, amount and chemical composition of a meal. Ingestion of a meal triggers a number of sensory signals in the gastrointestinal tract. These include the response to mechanical stimulation (e.g., gastric distension), from the presence of food in the gut, and the interaction of various dietary nutrients with specific “taste” receptors on specialized enteroendocrine cells in the small intestine culminating in the release of gut hormones. These signals are then transmitted to the brain where they contribute to food intake regulation by modulating appetite as well as feedback control of gastrointestinal functions (e.g., gut motility). There is evidence that the sensitivity to these food related stimuli is abnormally enhanced in functional dyspepsia leading to symptoms such nausea and bloating. In addition, these gut-brain signals can modulate the signaling pathways involved in visceral pain. This review will discuss the role of gut-brain signals in appetite regulation and the role dysregulation of this system play in functional dyspepsia.

In a recent study, Belin et al. demonstrated that glycine-bound NMDA receptors can be activated by mechanical forces in the absence of the neurotransmitter glutamate. The stretch-gated receptor exhibits biophysical properties similar to those of glutamate-gated receptors. These findings reveal that glycine-bound NMDA receptors could behave as mechanosensors in central nervous system (CNS) physiology. [ABSTRACT FROM AUTHOR]

The oriental armyworm, Mythimna separata (Walker), is a polyphagous, migratory pest relying on olfactory cues to find mates, locate nectar, and guide long-distance flight behavior. In the present study, a combination of neuroanatomical techniques were utilized on this species, including backfills, confocal microscopy, and three-dimensional reconstructions, to trace the central projections of sensory neurons from the antenna and the labial pit organ, respectively. As previously shown, the axons of the labial sensory neurons project via the ipsilateral labial nerve and terminate in three main areas of the central nervous system: (1) the labial-palp pit organ glomerulus of each antennal lobe, (2) the gnathal ganglion, and (3) the prothoracic ganglion of the ventral nerve cord. Similarly, the antennal sensory axons project to multiple areas of the central nervous system. The ipsilateral antennal nerve targets mainly the antennal lobe, the antennal mechanosensory and motor center, and the prothoracic and mesothoracic ganglia. Specific staining experiments including dye application to each of the three antennal segments indicate that the antennal lobe receives input from flagellar olfactory neurons exclusively, while the antennal mechanosensory and motor center is innervated by mechanosensory neurons from the whole antenna, comprising the flagellum, pedicle, and scape. The terminals in the mechanosensory and motor center are organized in segregated zones relating to the origin of neurons. The flagellar mechanosensory axons target anterior zones, while the pedicular and scapal axons terminate in posterior zones. In the ventral nerve cord, the processes from the antennal sensory neurons terminate in the motor area of the thoracic ganglia, suggesting a close connection with motor neurons. Taken together, the numerous neuropils innervated by axons both from the antenna and labial palp indicate the multiple roles these sensory organs serve in insect behavior.

In living organisms, changes in calcium flux are integral to many different cellular functions and are especially critical for the activity of neurons and myocytes. Genetically encoded calcium indicators (GECIs) have been popular tools for reporting changes in calcium levels in vivo. In particular, GCaMPs, derived from GFP, are the most widely used GECIs and have become an invaluable toolkit for neurophysiological studies. Recently, new variants of GCaMP, which offer a greater variety of temporal dynamics and improved brightness, have been developed. However, these variants are not readily available to the Caenorhabditis elegans research community. This work reports a set of GCaMP6 and jGCaMP7 reporters optimized for C. elegans studies. Our toolkit provides reporters with improved dynamic range, varied kinetics, and targeted subcellular localizations. Besides optimized routine uses, this set of reporters is also well suited for studies requiring fast imaging speeds and low magnification or low-cost platforms., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Snakes can bend their elongate bodies in various forms to traverse various environments. We understand well how snakes use lateral body bending to push against asperities on flat ground for propulsion, and snake robots can do so effectively. However, snakes can also use vertical bending to push against uneven terrain of large height variation for propulsion, and they can adjust this bending to adapt to novel terrain presumably using mechano-sensing feedback control. Although some snake robots can traverse uneven terrain, few have used vertical bending for propulsion, and how to control this process in novel environments is poorly understood. Here we systematically studied a snake robot with force sensors pushing against large bumps using vertical bending to understand the role of sensory feedback control. We compared a feedforward controller and four feedback controllers that use different sensory information and generate distinct bending patterns and body-terrain interaction. We challenged the robot with increasing backward load and novel terrain geometry that break its contact with the terrain. We further varied how much the feedback control modulated body bending to conform to or push against the terrain to test their effects. Feedforward propagation of vertical bending generated large propulsion when the bending shape matched terrain geometry. However, when perturbations caused loss of contact, the robot easily lost propulsion or had motor overload. Contact feedback control resolved these issues by helping the robot regain contact. Yet excessive conformation interrupted shape propagation and excessive pushing stalled motors frequently. Unlike that using lateral bending, for propulsion generation using vertical bending, body weight that can help maintain contact with the environment but may also overload motors. Our results will help snake robots better traverse uneven terrain with large height variation and can inform how snakes use sensory feedback to control vertical body bending for propulsion., (Creative Commons Attribution license.)

Cells sense and respond to mechanical stimuli by converting those stimuli into biological signals, a process known as mechanotransduction. Mechanotransduction is essential in diverse cellular functions, including tissue development, touch sensitivity, pain, and neuronal pathfinding. In the search for key players of mechanotransduction, several families of ion channels were identified as being mechanosensitive and were demonstrated to be activated directly by mechanical forces in both the membrane bilayer and the cytoskeleton. More recently, Piezo ion channels were discovered as a bona fide mechanosensitive ion channel, and its characterization led to a cascade of research that revealed the diverse functions of Piezo proteins and, in particular, their involvement in neuronal repair.

The lateral line system of zebrafish consists of the anterior lateral line, with neuromasts distributed on the head, and the posterior lateral line, with neuromasts distributed on the trunk. The sensory afferent neurons are contained in the anterior and posterior lateral line ganglia, respectively. So far, the vast majority of physiological and developmental studies have focused on the posterior lateral line. However, studies that focus on the anterior lateral line, especially on its physiology, are very rare. The anterior lateral line involves different neuromast patterning processes, specific distribution of synapses, and a unique role in behavior. Here, we report our observations regarding the development of the lateral line and analyze the physiological responses of the anterior lateral line to mechanical and water jet stimuli. Sensing in the fish head may be crucial to avoid obstacles, catch prey, and orient in water current, especially in the absence of visual cues. Alongside the lateral line, the trigeminal system, with its fine nerve endings innervating the skin, could contribute to perceiving mechanosensory stimulation. Therefore, we compare the physiological responses of the lateral line afferent neurons to responses of trigeminal neurons and responsiveness of auditory neurons. We show that anterior lateral line neurons are tuned to the velocity of mechanosensory ramp stimulation, while trigeminal neurons either only respond to mechanical step stimuli or fast ramp and step stimuli. Auditory neurons did not respond to mechanical or water jet stimuli. These results may prove to be essential in designing underwater robots and artificial lateral lines, with respect to the spectra of stimuli that the different mechanosensory systems in the larval head are tuned to, and underline the importance and functionality of the anterior lateral line system in the larval fish head., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brehm, Wenke, Glessner and Haehnel-Taguchi.)

In addition to their well-described functions in cell excitability, voltage-sensitive calcium channels (VSCCs) serve a critical role in calcium (Ca 2+ )-mediated secretion of pleiotropic paracrine and endocrine factors, including those produced in bone. Influx of Ca 2+ through VSCCs activates intracellular signaling pathways to modulate a variety of cellular processes that include cell proliferation, differentiation, and bone adaptation in response to mechanical stimuli. Less well understood is the role of VSCCs in the control of bone and calcium homeostasis mediated through secreted factors. In this review, we discuss the various functions of VSCCs in skeletal cells as regulators of Ca 2+ dynamics and detail how these channels might control the release of bioactive factors from bone cells. Because VSCCs are druggable, a better understanding of the multiple functions of these channels in the skeleton offers the opportunity for developing new therapies to enhance and maintain bone and to improve systemic health., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

During locomotion, animals rely on multiple sensory modalities to maintain stability. External cues may guide behaviour, but they must be interpreted in the context of the animal's own body movements. Mechanosensory cues that can resolve dynamic internal and environmental conditions, like those from vertebrate vestibular systems or other proprioceptors, are essential for guided movement. How do afferent proprioceptor neurons transform movement into a neural code? In flies, modified hindwings known as halteres detect forces produced by body rotations and are essential for flight. However, the mechanisms by which haltere neurons transform forces resulting from three-dimensional body rotations into patterns of neural spikes are unknown. We use intracellular electrodes to record from haltere primary afferent neurons during a range of haltere motions. We find that spike timing activity of individual neurons changes with displacement and propose a mechanism by which single neurons can encode three-dimensional haltere movements during flight. [ABSTRACT FROM AUTHOR]

Mechanical sensing is important for all organisms, but is the least understood of the senses. As mechanical stimuli come in diverse forms, organisms often have sensors or sensory systems that specialise in a form of mechanical stimuli, such as touch or vibration. Here, we tested the hypothesis that the nematode worm Caenorhabditis elegans exhibits a behavioural response to vibration that is distinct from its responses to touch. We show that wild-type strain worms respond to sustained low-frequency vibration in a manner distinct from the known responses to non-localised mechanical stimuli. Furthermore, the behavioural responses of mutant strains suggest different roles for ciliated versus non-ciliated neurons in mediating the response. Although further study is required to identify the vibration-sensing pathway, our data support that C. elegans can sense substrate-borne vibrations using cells distinct from those used in gentle touch. [ABSTRACT FROM AUTHOR]

The upper gastrointestinal tract plays an important role in sensing the arrival, amount and chemical composition of a meal. Ingestion of a meal triggers a number of sensory signals in the gastrointestinal tract. These include the response to mechanical stimulation (e.g., gastric distension), from the presence of food in the gut, and the interaction of various dietary nutrients with specific "taste" receptors on specialized enteroendocrine cells in the small intestine culminating in the release of gut hormones. These signals are then transmitted to the brain where they contribute to food intake regulation by modulating appetite as well as feedback control of gastrointestinal functions (e.g., gut motility). There is evidence that the sensitivity to these food related stimuli is abnormally enhanced in functional dyspepsia leading to symptoms such nausea and bloating. In addition, these gut-brain signals can modulate the signaling pathways involved in visceral pain. This review will discuss the role of gut-brain signals in appetite regulation and the role dysregulation of this system play in functional dyspepsia. [ABSTRACT FROM AUTHOR]

Focused ultrasound has been shown to stimulate excitable cells, but the biophysical mechanisms behind this phenomenon remain poorly understood. To provide additional insight, we devised a behavioral-genetic assay applied to the well-characterized nervous system of Caenorhabditis elegans nematodes. We found that pulsed ultrasound elicits robust reversal behavior in wild type animals in a pressure-, duration-, and pulse protocol-dependent manner. Responses were preserved in mutants unable to sense thermal fluctuations and absent in mutants lacking neurons required for mechanosensation. Additionally, we found that the worm's response to ultrasound pulses rests on the expression of MEC-4, a DEG/ENaC/ASIC ion channel required for touch sensation. Consistent with prior studies of MEC-4-dependent currents in vivo, the worm's response was optimal for pulses repeated 300 -1000 times per second. Based on these findings, we conclude that mechanical, rather than thermal, stimulation accounts for behavioral responses. Further, we propose that acoustic radiation force governs the response to ultrasound in a manner that depends on the touch receptor neurons and MEC-4-dependent ion channels. Our findings illuminate a complete pathway of ultrasound action, from the forces generated by propagating ultrasound to an activation of a specific ion channel. The findings further highlight the importance of optimizing ultrasound pulsing protocols when stimulating neurons via ion channels with mechanosensitive properties. [ABSTRACT FROM AUTHOR]

Neurons allocated to sense organs respond rapidly to mechanical signals dictating behavioral responses at the organism level. The receptors that transduce these signals, and underlie these senses, are mechanically gated channels. Research on mechanosensation over the past decade, employing in many cases Drosophila as a model, has focused in typifying these receptors and in exploring the different ways, depending on context, in which these mechanosensors are modulated. In this review, we discuss first what we have learned from Drosophila on these mechanisms and we describe the different mechanosensory organs present in the Drosophila larvae and adult. Secondly, we focus on the progress obtained by studying the fly on the characterization of the mechanosensory crosstalk underlying complex behaviors like motor coordination. Finally, turning to a cellular level, we summarize what is known on the mechanical properties and sensing capabilities of neural cells and how they may affect neural physiology and pathology. [ABSTRACT FROM AUTHOR]

Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin-4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein’s actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis. [ABSTRACT FROM AUTHOR]

Primary cilia are microtubule-based organelles presenting on the surface of most postmitotic mammalian cells. As being signaling hubs and sensory organelles, primary cilia can respond to mechanical and chemical stimuli from the extracellular environment. Arl13b (ADP-ribosylation factor-like 13B), an atypical Arf/Arl family GTPase, was identified in genetic screening as a protein essential for maintaining the integrity of cilia and neural tubes. Previous studies on Arl13b have mostly focused on its role in the development of neural tubes, polycystic kidneys, and tumors, but no role in bone patterns was described. This study reported the essential roles of Arl13b in bone formation and osteogenic differentiation. Arl13b was highly expressed in bone tissues and osteoblasts, positively correlated with osteogenic activity during bone development. Furthermore, Arl13b was essential for primary cilium maintenance and Hedgehog signaling activation in osteoblasts. Arl13b knockdown in osteoblasts decreased the length of primary cilia and the upregulated levels of Gli1, Smo, and Ptch1 upon Smo agonist treatment. Additionally, Arl13b knockdown inhibited cell proliferation and migration. Moreover, Arl13b mediated osteogenesis and cell mechanosensation. Cyclic tension strain upregulated the Arl13b expression. Arl13b knockdown suppressed osteogenesis and mitigated cyclic tension strain-induced osteogenesis. These results suggest that Arl13b have important roles in bone formation and mechanosensation. [Display omitted] • Arl13b enriches in cells around bone surface and positively correlated with osteogenesis during bone development. • Arl13b promotes the proliferation, migration and osteogenesis in osteoblasts. • Arl13b may serve as a mechanosensitive molecule mediating osteogenesis. [ABSTRACT FROM AUTHOR]

The nematode C. elegans uses mechanosensitive neurons to detect bacteria, which are food for worms. These neurons release dopamine to suppress foraging and promote dwelling. Through a screen of genes highly expressed in dopaminergic food-sensing neurons, we identify a K2P-family potassium channel—TWK-2—that damps their activity. Strikingly, loss of TWK-2 restores mechanosensation to neurons lacking the NOMPC-like channel transient receptor potential 4 (TRP-4), which was thought to be the primary mechanoreceptor for tactile food sensing. The alternate mechanoreceptor mechanism uncovered by TWK-2 mutation requires three Deg/ENaC channel subunits: ASIC-1, DEL-3, and UNC-8. Analysis of cell-physiological responses to mechanostimuli indicates that TRP and Deg/ENaC channels work together to set the range of analog encoding of stimulus intensity and to improve signal-to-noise characteristics and temporal fidelity of food-sensing neurons. We conclude that a specialized mechanosensory modality—tactile food sensing—emerges from coordination of distinct force-sensing mechanisms housed in one type of sensory neuron. [Display omitted] • C. elegans dopamine neurons are mechanosensors that govern food-response behaviors • The K2P channel TWK-2 is a negative regulator of dopaminergic mechanosensors • Loss of TWK-2 channels reveals a role for Deg/ENaC channels in dopaminergic mechanosensors • Deg/ENaC and TRP channels coordinately determine the fidelity of tactile food sensing The nematode C. elegans uses specialized mechanosensory neurons to detect food. Fok et al. find that these neurons require a K2P channel and Deg/ENaC channels in addition to TRP channels for high-fidelity responses to mechanostimuli and normal food-response behavior. [ABSTRACT FROM AUTHOR]

Background/Objective: Tooth eruption is a foundational subject for every dental practitioner as well as dental students; and literature is replete with different mechanisms of migration of a tooth from its bony crypt into the oral cavity. The purpose of the part two of this study was to evaluate and test the proposed “neuromuscular theory of tooth eruption” using relevant scientific papers, as supporting bodies of evidence, to unify the currently accepted mechanisms of tooth eruption under single theory. Materials and Methods: A detailed and systematic analysis, synthesis and integration of the findings from relevant scientific studies (selected according to specific inclusion and exclusion criteria) on mechanisms of tooth eruption was conducted as it was done with part one of this study. Results: The propelling force of tooth eruption is attributed to piezoelectricity, mechanosensation, mechanotransduction, mechanical pull on the hydroxyapatite crystals; mechano-hydrodynamic force; and mechanics of the mandible and the orofacial muscles with attendant biochemical, electrical, electrochemical, cellular, molecular and enzymic activities to prepare the jaws and other facial bones for coronal migration of a developing tooth from its bony crypt until it emerges in the oral cavity. Conclusion: “Neuromuscular theory of tooth eruption” is based on neuromuscular forces, arising from muscular contractions in the orofacial region. Mechanosensation, mechanotransduction and piezoelectricity are the three principal processes of converting neuromuscular forces into electrical, electrochemical and biochemical energies for initiation and sustenance of cellular, molecular and enzymic activities during the different phases of tooth eruption process. The clinical relevance of this theory is that it throws more light on the morphological and functional interdependence of the various elements of the maxillo-mandibulo-dental system as well as the need for neuromuscular considerations in the diagnosis, treatment planning, prevention and treatment of pathological conditions of tooth eruption. Key words: Mechanosensation, Mechanotransduction, Neuromuscular, Theory, Tooth eruption.