Explore the vast range of titles available.

The stretch-activated channel Piezo1 controls homeostatic epithelial cell numbers by activating cells to divide rapidly when under stretch strain from low density, and by activating cells to extrude and die when cells are under crowding strain. Cell division in response to mechanical stress Epithelial cell layers serve as barriers for the organs they cover, yet they continuously undergo cell division and cell death. So how do these dynamic processes avoid compromising the barrier function of epithelia? Jody Rosenblatt and colleagues previously reported in Nature that when epithelial cells become too crowded they trigger the stretch-activated channel Piezo1 to effect extrusion of cells that later die. They now ask how epithelia deal with the opposite situation—cell death. It emerges that, following cell death, the low density of surrounding cells also activate Piezo1, driving cell division to rebalance the cell numbers. The authors provide insights into the molecular mechanism through which stretch triggers cell division, and propose that whether Piezo1 signals for cell division or cell extrusion depends on the type of mechanical forces that it experiences. Despite acting as a barrier for the organs they encase, epithelial cells turn over at some of the fastest rates in the body. However, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How does the number of dying cells match those dividing to maintain constant numbers? When epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die 1 . However, it is unclear how epithelial cell division is controlled to balance cell death at the steady state. Here we show that mammalian epithelial cell division occurs in regions of low cell density where cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the Piezo1 channel. To stimulate cell division, stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at the steady state, the type of mechanical force controls the outcome: stretch induces cell division, whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion and apoptosis in crowded regions and cell division in sparse regions.

Glutamate is traditionally viewed as the first messenger to activate NMDAR ( N -methyl- d -aspartate receptor)-dependent cell death pathways in stroke 1 , 2 , but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms 3 – 7 . Here we show that glutamate and its structural analogues, including NMDAR antagonist l -AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke 4 . Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels 4 – 7 . We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists. Glutamate functions as a positive allosteric modulator for acid-sensing ion channels to exacerbate ischaemic neurotoxicity.

Uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue is supported by a burst of mitochondrial reactive oxygen species upon cold exposure. Control of brown fat thermogenesis Thermogenic respiration in brown adipose tissue (BAT) and beige fat relies on the uncoupling protein 1 (UCP1), a mitochondrial inner membrane protein that produces heat by dissipating the mitochondrial proton gradient generated by the respiratory chain. These authors show that UCP1 activation is supported by a burst of mitochondrial reactive oxygen species (ROS) upon cold exposure. ROS are necessary to sulfenylate a critical cysteine residue in UCP1, which drives its activation — in effect, the 'on/off switch' for UCP1. Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1) 1 , 2 . Thermogenesis from these adipocytes can combat obesity and diabetes 3 , encouraging investigation of factors that control UCP1-dependent respiration in vivo . Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.

A mouse study shows that non-neuronal epidermal Merkel cells aid fine-touch perception in the skin through their expression of the Piezo2 mechanosensitive cation channel which then actively tunes the response to touch in adjacent somatosensory neurons. Non-neural Merkel cells stay in touch Merkel cells (also known as Merkel-Ranvier cells) are found in the vertebrate epidermis. They are non-neuronal but may make 'synapse-like' contact with neighbouring cells. It has been suggested that they are associated with the sensation of touch, but this has been difficult to prove and remains controversial. In this week's Nature two teams present clear evidence that Merkel cells are autonomous mechanosensors essential to fine touch perception. The cells express the mechanosensitive channel Piezo2, which allows them to actively tune somatosensory neurons' responses to touch. These results are consistent with a compound receptor system model in which epidermal cells help neurons to discriminate between different types of touch — such as flutter, stretch and pressure — and therefore to decode the fine details of objects. How we sense touch remains fundamentally unknown 1 , 2 . The Merkel cell–neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Aβ sensory fibres to encode fine details of objects 3 , 4 , 5 , 6 . This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago 3 , 4 . However, whether Merkel cells or afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown 1 , 2 , 7 , 8 , 9 , 10 , 11 , 12 . Synapse-like junctions are observed between Merkel cells and associated afferents 6 , 13 , 14 , 15 , and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve 1 , 2 , 16 , 17 . Here we show that Merkel cells produce touch-sensitive currents in vitro . Piezo2, a mechanically activated cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel-cell mechanosensitivity completely depends on Piezo2. In these mice, slowly adapting responses in vivo mediated by the Merkel cell–neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus 15 , 18 , 19 .

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2 + vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering–Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults. The mechanoreceptor Piezo2 is required for both the Hering–Breuer inflation reflex in adult mice and the inflation of the lungs of newborn mice. Role of mechanotransduction in breathing The Hering–Breuer inflation reflex, described some 150 years ago, is thought to protect the lung from overinflation thanks to stretch-activated sensory neurons that innervate the lung, but the actual molecular and cellular mechanisms involved have remained unknown. Ardem Patapoutian and colleagues find that this reflex is absent in adult mice that lack the mechanosensitive ion channel Piezo2, which was previously implicated in the skin's sense of touch. Surprisingly, Piezo2 is also required for initial lung inflation at birth, thus establishing a role for mechanotransduction in respiratory control in both newborn and adult mice.

Proprioception, the sense of body and limb position, begins in nerve cells called proprioceptors that are activated by muscle or joint stretch. The molecular mechanism of mechanotransduction in mammalian proprioceptors is unknown. The authors show that the mechanically activated cation channel Piezo2 is the principal mechanotransducer in murine proprioceptors. Proprioception, the perception of body and limb position, is mediated by proprioceptors, specialized mechanosensory neurons that convey information about the stretch and tension experienced by muscles, tendons, skin and joints. In mammals, the molecular identity of the stretch-sensitive channel that mediates proprioception is unknown. We found that the mechanically activated nonselective cation channel Piezo2 was expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs in mice. Two independent mouse lines that lack Piezo2 in proprioceptive neurons showed severely uncoordinated body movements and abnormal limb positions. Moreover, the mechanosensitivity of parvalbumin-expressing neurons that predominantly mark proprioceptors was dependent on Piezo2 expression in vitro , and the stretch-induced firing of proprioceptors in muscle-nerve recordings was markedly reduced in Piezo2-deficient mice. Together, our results indicate that Piezo2 is the major mechanotransducer of mammalian proprioceptors.

Animals use their muscles to shiver to generate heat when exposed to the cold. But this is a short-term adaptation. Long term, it is believed the body relies on the brown adipose tissue (BAT) to generate heat in a nonshivering fashion. New work from Muthu Periasamy and colleagues challenge this BAT-centric view by showing that the muscle is also a key site of nonshivering thermogenesis. The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca 2+ -ATPase (Serca) pump 1 , 2 , 3 , 4 , 5 , is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln −/− mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca 2+ leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca 2+ , which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.

Here it is shown that epithelia extrude live but not dying cells at sites of high strain, elucidating a mechanism for maintaining homeostatic cell numbers. Crowd control in epithelia For an epithelial-cell layer to retain its structure and provide a protective barrier, it needs to maintain a balance between the number of cells dividing and the number dying. Buzz Baum and colleagues study this process in Drosophila tissues and demonstrate a direct link between physical forces in a tissue and the rates of cell loss. In regions of tissue that are overcrowded, some of the cells undergo a loss of cell-adhesive junctions and are squeezed out by neighbouring cells. This process of live-cell delamination buffers epithelial cells against variations in growth and contributes to normal tissue homeostasis. As a link between epithelial hyperplasia and cell invasion, it may have relevance to the early stages of cancer development. In a second paper, Jody Rosenblatt and colleagues study epithelial-cell monolayers and find that epithelia extrude live but not dying cells at sites of high strain. The extruded cells undergo cell death owing to loss of survival factors. Hence, extrusion could provide a tumour-suppressive mechanism that could be used to eliminate excess cells. In carcinomas with high levels of survival signalling pathways, extrusion may promote tumour-cell invasion. For an epithelium to provide a protective barrier, it must maintain homeostatic cell numbers by matching the number of dividing cells with the number of dying cells. Although compensatory cell division can be triggered by dying cells 1 , 2 , 3 , it is unknown how cell death might relieve overcrowding due to proliferation. When we trigger apoptosis in epithelia, dying cells are extruded to preserve a functional barrier 4 . Extrusion occurs by cells destined to die signalling to surrounding epithelial cells to contract an actomyosin ring that squeezes the dying cell out 4 , 5 , 6 . However, it is not clear what drives cell death during normal homeostasis. Here we show in human, canine and zebrafish cells that overcrowding due to proliferation and migration induces extrusion of live cells to control epithelial cell numbers. Extrusion of live cells occurs at sites where the highest crowding occurs in vivo and can be induced by experimentally overcrowding monolayers in vitro . Like apoptotic cell extrusion, live cell extrusion resulting from overcrowding also requires sphingosine 1-phosphate signalling and Rho-kinase-dependent myosin contraction, but is distinguished by signalling through stretch-activated channels. Moreover, disruption of a stretch-activated channel, Piezo1, in zebrafish prevents extrusion and leads to the formation of epithelial cell masses. Our findings reveal that during homeostatic turnover, growth and division of epithelial cells on a confined substratum cause overcrowding that leads to their extrusion and consequent death owing to the loss of survival factors. These results suggest that live cell extrusion could be a tumour-suppressive mechanism that prevents the accumulation of excess epithelial cells.

Acid-sensing ion channel 3 (ASIC3) is involved in acid nociception, but its possible role in neurosensory mechanotransduction is disputed. We report here the generation of Asic3-knockout/eGFPf-knockin mice and subsequent characterization of heterogeneous expression of ASIC3 in the dorsal root ganglion (DRG). ASIC3 is expressed in parvalbumin (Pv+) proprioceptor axons innervating muscle spindles. We further generate a floxed allele of Asic3 ( Asic3 f/f ) and probe the role of ASIC3 in mechanotransduction in neurite-bearing Pv+ DRG neurons through localized elastic matrix movements and electrophysiology. Targeted knockout of Asic3 disrupts spindle afferent sensitivity to dynamic stimuli and impairs mechanotransduction in Pv+ DRG neurons because of substrate deformation-induced neurite stretching, but not to direct neurite indentation. In behavioural tasks, global knockout ( Asic3 −/− ) and Pv-Cre::Asic3 f/f mice produce similar deficits in grid and balance beam walking tasks. We conclude that, at least in mouse, ASIC3 is a molecular determinant contributing to dynamic mechanosensitivity in proprioceptors. Acid-sensing ion channel 3 (ASIC3) is known to play a role in nociception, but its role in low threshold neurosensory mechanotransduction is unclear. Here, the authors target ASIC3 expression in dorsal root ganglion parvalbumin positive neurons and find ASIC3 contributes to dynamic proprioception responses.

Exposure to psychostimulants such as cocaine induces synaptic plasticity within the nucleus accumbens (NAc) and alters behavior. Here the authors find a new role for the acid-sensing channel 1A (ASIC1A) in excitatory transmission and plasticity within the NAc that contributes to cocaine-induced learning and self-administration. Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.