Intercellular Signaling Pathways Research Articles

Evolution of vertebrate spinal cord patterning.

The vertebrate spinal cord is organized across three developmental axes, anterior-posterior (AP), dorsal-ventral (DV), and medial-lateral (ML). Patterning of these axes is regulated by canonical intercellular signaling pathways: the AP axis by Wnt, fibroblast growth factor, and retinoic acid (RA), the DV axis by Hedgehog, Tgfβ, and Wnt, and the ML axis where proliferation is controlled by Notch. Developmental time plays an important role in which signal does what and when. Patterning across the three axes is not independent, but linked by interactions between signaling pathway components and their transcriptional targets. Combined this builds a sophisticated organ with many different types of cell in specific AP, DV, and ML positions. Two living lineages share phylum Chordata with vertebrates, amphioxus, and tunicates, while the jawless fish such as lampreys, survive as the most basally divergent vertebrate lineage. Genes and mechanisms shared between lampreys and other vertebrates tell us what predated vertebrates, while those also shared with other chordates tell us what evolved early in chordate evolution. Between these lie vertebrate innovations: genetic and developmental changes linked to evolution of new morphology. These include gene duplications, differences in how signals are received, and new regulatory connections between signaling pathways and their target genes.

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

In prostate cancer, cancer-associated fibroblasts (CAF) exhibit contrasting biological properties to non-malignant prostate fibroblasts (NPF) and promote tumorigenesis. Resolving intercellular signaling pathways between CAF and prostate tumor epithelium may offer novel opportunities for research translation. To this end, the proteome and phosphoproteome of four pairs of patient-matched CAF and NPF were characterized to identify discriminating proteomic signatures. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a hyper reaction monitoring data-independent acquisition (HRM-DIA) workflow. Proteins that exhibited a significant increase in CAF versus NPF were enriched for the functional categories "cell adhesion" and the "extracellular matrix." The CAF phosphoproteome exhibited enhanced phosphorylation of proteins associated with the "spliceosome" and "actin binding." STRING analysis of the CAF proteome revealed a prominent interaction hub associated with collagen synthesis, modification, and signaling. It contained multiple collagens, including the fibrillar types COL1A1/2 and COL5A1; the receptor tyrosine kinase discoidin domain-containing receptor 2 (DDR2), a receptor for fibrillar collagens; and lysyl oxidase-like 2 (LOXL2), an enzyme that promotes collagen crosslinking. Increased activity and/or expression of LOXL2 and DDR2 in CAF were confirmed by enzymatic assays and Western blotting analyses. Pharmacological inhibition of CAF-derived LOXL2 perturbed extracellular matrix (ECM) organization and decreased CAF migration in a wound healing assay. Further, it significantly impaired the motility of co-cultured RWPE-2 prostate tumor epithelial cells. These results indicate that CAF-derived LOXL2 is an important mediator of intercellular communication within the prostate tumor microenvironment and is a potential therapeutic target.

Identifying Plasma Derived Extracellular Vesicle (EV) Contained Biomarkers in the Development of Chronic Neuropathic Pain

Research into potentially novel biomarkers for chronic pain development is lacking. microRNAs (miRNAs) are attractive candidates as biomarkers due to their conservation across species, stability in liquid biopsies, and variation that corresponds to a pathologic state. miRNAs can be sorted into extracellular vesicles (EVs) within the cell and released from the site of injury. EVs transfer cargo molecules between cells thus affecting key intercellular signaling pathways. The focus of this study was to determine the plasma derived EV miRNA content in a chronic neuropathic pain rat model. This was accomplished by performing either spinal nerve ligation (SNL; n = 6) or sham (n = 6) surgery on anesthetized male Sprague-Dawley rats. Mechanosensitivity was assessed and plasma derived EV RNA was isolated at baseline (BL), day 3, and 15 postnerve injury. EV extracted small RNA was sequenced followed by differentially expressed (DE) miRNAs and gene target enrichment/signaling pathway analysis performed using R packages and TargetScan/Ingenuity pathway analysis (IPA), respectively. Seven of the DE miRNAs were validated by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). The data indicated that SNL rats displayed a time-dependent threshold reduction in response to evoked stimuli from day 3 to day 15 postnerve injury. The data also revealed that 22 and 74 miRNAs at day 3 and 15, respectively, and 33 miRNAs at both day 3 and 15 were uniquely DE between the SNL and sham groups. The key findings from this proposal include (1) the majority of the DE EV miRNAs, which normally function to suppress inflammation, were downregulated, and (2) several of the plasma derived DE EV miRNAs reflect previously observed changes in the injured L5 nerve. The plasma derived DE EV miRNAs regulate processes important in the development and maintenance of neuropathic pain states and potentially serve as key regulators, biomarkers, and targets in the progression and treatment of chronic neuropathic pain. PerspectiveThis article describes the DE miRNA content of plasma derived EVs, comparing neuropathic pain to normal conditions. This data indicates that EV miRNAs may be important in nociception and may also serve as biomarkers for chronic pain. These results encourage further research on EV miRNAs in chronic neuropathic pain sufferers.

Communication codes in developmental signaling pathways.

A handful of core intercellular signaling pathways play pivotal roles in a broad variety of developmental processes. It has remained puzzling how so few pathways can provide the precision and specificity of cell-cell communication required for multicellular development. Solving this requires us to quantitatively understand how developmentally relevant signaling information is actively sensed, transformed and spatially distributed by signaling pathways. Recently, single cell analysis and cell-based reconstitution, among other approaches, have begun to reveal the 'communication codes' through which information is represented in the identities, concentrations, combinations and dynamics of extracellular ligands. They have also revealed how signaling pathways decipher these features and control the spatial distribution of signaling in multicellular contexts. Here, we review recent work reporting the discovery and analysis of communication codes and discuss their implications for diverse developmental processes.

Evaluating measures of association for single-cell transcriptomics.

Single-cell transcriptomics provides an opportunity to characterize cell-type-specific transcriptional networks, intercellular signaling pathways and cellular diversity with unprecedented resolution by profiling thousands of cells in a single experiment. However, owing to the unique statistical properties of scRNA-seq data, the optimal measures of association for identifying gene-gene and cell-cell relationships from single-cell transcriptomics remain unclear. Here, we conducted a large-scale evaluation of 17 measures of association for their ability to reconstruct cellular networks, cluster cells of the same type and link cell-type-specific transcriptional programs to disease. Measures of proportionality were consistently among the best-performing methods across datasets and tasks. Our analysis provides data-driven guidance for gene and cell network analysis in single-cell transcriptomics.

Notch1 mediates acute colitis by downregulating IL17 and IL22 cytokines and cross talking with NFkB pathway

IntroductionUlcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes chronic inflammation and ulcers affecting the innermost lining of colon and rectum. Almost 1 million people suffer through UC in the United States alone, with a disease history of 16 years. Notch1 signaling is an evolutionarily conserved intercellular signaling pathway. It regulates cell fate, cell proliferation, cell differentiation, and cell death. However, Notch1 can act as a mediator or suppressor depending on the cellular context and disease stage.AimAim of this study is to understand the mechanistic role of Notch1 in UC.MethodsWe used 7 weeks old (both male and female) transgenic mice (C57/B6) with conditional deletion of Notch1 under villin promoter (Ncre). Notch1flox/flox mice (Nflox) were used as the control group since they were crossed with Crevillin mice to generate Ncre mice. Enteroids were isolated from 6 weeks old Ncre and Nflox mice to study proliferation and differentiation. Colonic inflammation was induced by the inflammatory agent dextran sodium sulfate (2.5% in drinking water for 5 days). Colonic tissues were used for western blot (WB) analysis and histochemistry.ResultsWB analysis showed that Notch1 signaling was absent in colon, small intestine, spleen and cecum of Ncre mice. However Notch 1 signaling was active in the liver of both Ncre and Nflox mice. In vivo permeability assay using 4kD FITC‐dextran showed that barrier function of Ncre mice was compromised compared to Nflox mice. Alcian blue ‐ periodic acid Schiff stain showed increased goblet cells among Ncre mice compared to Nflox mice. Enteroids isolated from Ncre and Nflox mice indicated compromised differentiation and altered proliferation among Ncre enteroids compared to Nflox ones on Days 2, 4 and 7. WB analysis exhibited decreased expression of PepT1 (enterocyte marker) and PCNA (proliferation maker) among Ncre enteroids compared to Nflox ones. We observed that Ncre mice were resistant to DSS induced colitis compared to Nflox mice as reflected by the body weight loss. Hematoxylin and Eosin staining exhibited decreased neutrophil infiltration, less damage to crypt architecture among Ncre mice compared to Nflox mice in acute colitis. QPCR analysis showed increased mRNA levels of IL6, TNFa, IL17 and IL22 cytokines among Ncre mice compared to Nflox mice in acute colitis. WBs indicated that Ncre mice had decreased expressions of NFkB and CyclinD (downstream target of NFkB and a proliferation marker). However there was no significant difference in protein expressions Cox2 or iNOS (inflammatory signaling pathways) among Ncre and Nflox mice as indicated by the WBs.ConclusionOur study shows that Notch1 mediates acute colitis by cross talking with NFkB pathway and promoting the abnormal proliferation. We also observed that Notch1 activation inhibits the activation of anti‐inflammatory cytokines (IL17 and IL22). However silencing of Notch1 signaling promotes goblet cell hyperplasia and inflammatory cytokines such as IL6 and TNFa. Therefore, our study suggests that instead of Notch1 silencing, NFkB inhibitors might be a better option as therapeutics for the colitis patients in the clinics.Support or Funding InformationNIDDK‐R01 Grant DK064711 to DM and 3057‐CCFAgrant to PGThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Role of Acrolein and NADPH Oxidase in the Granulocyte-Mediated Growth-Inhibition of Tumor Cells.

Although granulocytes are the most abundant leukocytes in human blood, their involvement in the immune response against cancer is not well understood. While granulocytes are known for their “oxidative burst” when challenged with tumor cells, it is less known that oxygen-dependent killing of tumor cells by granulocytes includes peroxidation of lipids in tumor cell membranes, yielding formation of reactive aldehydes like 4-hydroxynonenal (4-HNE) and acrolein. In the present work, we investigate the role of reactive aldehydes on cellular redox homeostasis and surface toll-like receptor 4 (TLR4) expression. We have further study the granulocyte-tumor cell intercellular redox signaling pathways. The data obtained show that granulocytes in the presence of 4-HNE and acrolein induce excessive ROS formation in tumor cells. Acrolein was also shown to induce granulocyte TLR4 expression. Furthermore, granulocyte-mediated antitumor effects were shown to be mediated via HOCl intracellular pathway by the action of NADPH oxidase. However, further studies are needed to understand interaction between TLR4 and granulocyte-tumor cell intercellular signaling pathways.

Protective Effects of Fermented Oyster Extract against RANKL-Induced Osteoclastogenesis through Scavenging ROS Generation in RAW 264.7 Cells.

Excessive bone resorption by osteoclasts causes bone loss-related diseases and reactive oxygen species (ROS) act as second messengers in intercellular signaling pathways during osteoclast differentiation. In this study, we explored the protective effects of fermented oyster extract (FO) against receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation in murine monocyte/macrophage RAW 264.7 cells. Our results showed that FO markedly inhibited RANKL-induced activation of tartrate-resistant acid phosphatase and formation of F-actin ring structure. Mechanistically, FO has been shown to down-regulate RANKL-induced expression of osteoclast-specific markers by blocking the nuclear translocation of NF-κB and the transcriptional activation of nuclear factor of activated T cells c1 (NFATc1) and c-Fos. Furthermore, FO markedly diminished ROS production by RANKL stimulation, which was associated with blocking the expression of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) and its regulatory subunit Rac-1. However, a small interfering RNA (siRNA) targeting NOX1 suppressed RANKL-induced expression of osteoclast-specific markers and production of ROS and attenuated osteoclast differentiation as in the FO treatment group. Collectively, our findings suggest that FO has anti-osteoclastogenic potential by inactivating the NF-κB-mediated NFATc1 and c-Fos signaling pathways and inhibiting ROS generation, followed by suppression of osteoclast-specific genes. Although further studies are needed to demonstrate efficacy in in vivo animal models, FO may be used as an effective alternative agent for the prevention and treatment of osteoclastogenic bone diseases.

Divergent proteomics response of Apostichopus japonicus suffering from skin ulceration syndrome and pathogen infection

Skin ulceration syndrome (SUS) of sea cucumber is a common and serious disease that affects the stable development of Apostichopus japonicus in the culture industry. The part of sea cucumber that suffers from major injury and is directly observed is the body wall, in which protein variations should be the most direct evidence of the disease. To understand the response mechanisms of A. japonicus in SUS progression, we investigated protein changes in the body wall of diseased A. japonicus induced by Vibrio splendidus and individuals with natural diseases by isobaric tags for relative and absolute quantification (iTRAQ). About 119 proteins were identified in the two iTRAQ groups. A comparison of the protein expression profiles among two SUS conditions revealed that the mode of action induced by V. splendidus (Vs-SUS) was completely different from those in individuals with natural disease (ND-SUS). Most of the differentially expressed proteins (DEPs) (33 in 37 DEPs) were significantly depressed in the Vs-SUS group. Only 13 proteins in 27 DEPs showed similar trend to those in the ND-SUS group. Many important proteins involved in major intercellular signaling pathways associated with SUS disease were identified based on the KEGG and GO database search. Many proteins were located in the mitochondria and mainly involved in the oxidative stress pathway. Glutathione metabolism pathway was associated with reactive oxygen (ROS) production in the ND-SUS group. In the Vs-group, most of the proteins were concentrated in the cytoplasm and were related to immunity and extracellular matrix stability. In the ND-SUS group, the activity of key enzymes (CAT, GPx) that eliminate mitochondrial ROS production and structural stable protein (HSP60, HSP10) decreased, whereas those of complement proteins (C3, C3-2) that promoted ROS production was upregulated. This finding supported that oxidative damage caused by ROS might be the main effector for SUS in the ND-SUS group. The challenge with V. splendidus led to the breakdown of the defense capability of sea cucumber and suppressed the expression of immune-related proteins, such as C-type lectin, caspase, STAT, and cystatin. The downregulation of TIMP led to MMP1 overexpression. Members of the MMP family could directly degrade the extracellular matrix, which may be the main reason for the cell matrix degradation and induced SUS disease in the Vs-SUS group. Hence, ROS and extracellular matrix degradation enzymes could play important roles in the formation of SUS in sea cucumber. Results provide insights into the complex molecular mechanism of SUS in sea cucumber.

Comparative analysis of CEACAM1 expression in thin melanomas with and without regression.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a key molecule in several intracellular and intercellular signaling pathways, with multiple functional and structural roles. CEACAM1 expression in melanoma is often described in the invading part of the tumor and has been associated with increased melanoma cells invasion and migration. We studied CEACAM1 expression in regressing versus non-regressing thin melanomas, knowing that phenomenon of regression represents a valuable model for understanding tumor immunity. In melanoma, through homophilic interactions, CEACAM1 inhibits natural killer cell activity, inhibits effector functions of tumor infiltrating lymphocytes, such as cytotoxicity and interferon-γ release. We present a retrospective study including 53 consecutive cases of thin melanoma, 21 with regression and 32 without regression. Comparative analysis of CEACAM1 expression in regressed and non-regressed areas from melanomas with regression and in non-regressed melanomas was performed. We used three different clones of CEACAM1: AA 1-428, extracellular domain, rabbit; AA 1-428, mouse, clone 8B6E2F4; and AA 1-468, full length, mouse, clone 2F6. All three clones had similar reactivity. We identified membrane positivity of tumor cells in non-regressed melanomas and in non-regressed areas in melanomas with regression. Remaining tumor cells in regressed areas were mostly negative for CEACAM1. In non-regressed lesions, there was a stronger positivity of CEACAM1 in the deep invasive front. In thin melanomas, CEACAM1 overexpression is related with invasiveness, suggesting that CEACAM1-positive melanomas are more aggressive. Also, in areas of regression tumor cells lose CEACAM1 expression, probably correlated with the presence of natural killer cells.

Crosstalk of Intercellular Signaling Pathways in the Generation of Midbrain Dopaminergic Neurons In Vivo and from Stem Cells.

Dopamine-synthesizing neurons located in the mammalian ventral midbrain are at the center stage of biomedical research due to their involvement in severe human neuropsychiatric and neurodegenerative disorders, most prominently Parkinson’s Disease (PD). The induction of midbrain dopaminergic (mDA) neurons depends on two important signaling centers of the mammalian embryo: the ventral midline or floor plate (FP) of the neural tube, and the isthmic organizer (IsO) at the mid-/hindbrain boundary (MHB). Cells located within and close to the FP secrete sonic hedgehog (SHH), and members of the wingless-type MMTV integration site family (WNT1/5A), as well as bone morphogenetic protein (BMP) family. The IsO cells secrete WNT1 and the fibroblast growth factor 8 (FGF8). Accordingly, the FGF8, SHH, WNT, and BMP signaling pathways play crucial roles during the development of the mDA neurons in the mammalian embryo. Moreover, these morphogens are essential for the generation of stem cell-derived mDA neurons, which are critical for the modeling, drug screening, and cell replacement therapy of PD. This review summarizes our current knowledge about the functions and crosstalk of these signaling pathways in mammalian mDA neuron development in vivo and their applications in stem cell-based paradigms for the efficient derivation of these neurons in vitro.

Signaling pathways involved in adaptive responses to cell membrane disruption.

Plasma membrane disruption occurs frequently in many animal tissues. Cell membrane disruption induces not only a rapid and massive influx of Ca2+ into the cytosol but also an efflux or release of various signaling molecules, such as ATP, from the cytosol; in turn, these signaling molecules stimulate a variety of pathways in both wounded and non-wounded neighboring cells. These signals first trigger cell membrane repair responses in the wounded cell but then induce an adaptive response, which results in faster membrane repair in the event of future wounds in both wounded and non-wounded neighboring cells. In addition, signaling pathways stimulated by membrane disruption induce other adaptive responses, including cell survival, regeneration, migration, and proliferation. This chapter summarizes the role of intra- and intercellular signaling pathways in adaptive responses triggered by cell membrane disruption.

Sequence environment of BMP-dependent activating elements controls transcriptional responses to Dpp signaling in Drosophila.

Intercellular signaling pathways activate transcription factors, which, along with tissue-specific co-factors, regulate expression of target genes. Responses to TGFβ/BMP signals are mediated by Smad proteins, which form complexes and accumulate in the nucleus to directly bind and regulate enhancers of BMP targets upon signaling. In Drosophila, gene activation by BMP signaling often requires, in addition to direct input by Smads, the signal-dependent removal of the transcriptional repressor Brk. Previous studies on enhancers of BMP-activated genes have defined a BMP-responsive motif, the AE, which integrates activatory and repressive input by the Smad complex and Brk, respectively. Here, we address whether sequence variations within the core AE sequences might endow the motif with additional properties accounting for qualitative and quantitative differences in BMP responses, including tissue specificity of transcriptional activation and differential sensitivity to Smad and Brk inputs. By analyzing and cross-comparing three distinct BMP-responsive enhancers from the genes wit and Dad in two different epithelia, the wing imaginal disc and the follicular epithelium, we demonstrate that differences in the AEs contribute neither to the observed tissue-restriction of BMP responses nor to differences in the utilization of the Smad and Brk branches for transcriptional activation. Rather, our results suggest that the cis-environment of the BMP-response elements not only dictates tissue specificity but also differential sensitivity to the two BMP mediators.

Wnt Signaling Pathway in Oral Lesions

Wingless-Integrated/Beta-catenin (WNT/-catenin) signalling pathway is one of the principal intercellular signalling pathways in humans. It plays an intrinsic role in the cellular proliferation, differentiation and regeneration along with many other cellular functions. Epigenetic deoxyribonucleic acid methylations and silencing of WNT signalling pathway genes have a significant role in malignant transformation of oral lesions such as oral submucous fibrosis, oral leukoplakia, oral lichen planus and erythroplakia. The increase in WNT inhibitory proteins along with inflammatory factors cause bone loss in periapical lesions, such as chronic apical periodontitis. This review discusses the molecular genetics of potentially malignant oral lesions, sheds light on our understanding of WNT/-catenin signalling in bone loss pertaining to periapical lesions, and alteration of this pathway for therapeutic benefits.

Notch and interacting signalling pathways in cardiac development, disease, and regeneration.

Cardiogenesis is a complex developmental process involving multiple overlapping stages of cell fate specification, proliferation, differentiation, and morphogenesis. Precise spatiotemporal coordination between the different cardiogenic processes is ensured by intercellular signalling crosstalk and tissue-tissue interactions. Notch is an intercellular signalling pathway crucial for cell fate decisions during multicellular organismal development and is aptly positioned to coordinate the complex signalling crosstalk required for progressive cell lineage restriction during cardiogenesis. In this Review, we describe the role of Notch signalling and the crosstalk with other signalling pathways during the differentiation and patterning of the different cardiac tissues and in cardiac valve and ventricular chamber development. We examine how perturbation of Notch signalling activity is linked to congenital heart diseases affecting the neonate and adult, and discuss studies that shed light on the role of Notch signalling in heart regeneration and repair after injury.

Dietary Lipids Modulate Notch Signaling and Influence Adult Intestinal Development and Metabolism in Drosophila

Tissue homeostasis involves a complex balance of developmental signals and environmental cues that dictate stem cell function. We found that dietary lipids control enteroendocrine cell production from Drosophila posterior midgut stem cells. Dietary cholesterol influences new intestinal cell differentiation in an Hr96-dependent manner by altering the level and duration of Notch signaling. Exogenous lipids modulate Delta ligand and Notch extracellular domain stability and alter their trafficking in endosomal vesicles. Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels. These diet-mediated alterations in young animals contribute to a metabolic program that persists after the diet changes. A low-sterol dietalso slows the proliferation of enteroendocrine tumors initiated by Notch pathway disruption. Thus, a specific dietary nutrient can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology.

Modern Concepts of Cholinergic Neurotransmission at the Motor Synapse

Cholinergic synaptic contact between motor neuron and skeletal muscle fiber is perhaps one of the core objects for investigations of molecular mechanisms underlying the communication between neurons and innervated cells. In the studies conducted on this object in the past few decades, a large amount of experimental data was obtained that substantially complemented a traditional view on synaptic transmission. In particular, it was established that (i) acetylcholine is released from the nerve ending in both quantal and nonquantal ways; (ii) molecular mechanisms of the processes of the quantal acetylcholine release—spontaneous and evoked by electrical stimuli—have unique features and can be regulated independently; (iii) acetylcholine release from the nerve ending is accompanied by a release of a number of synaptically active molecules modulating the processes of secretion or reception of the main mediator; (iv) signal molecules affecting the process of cholinergic neurotransmission can be released not only from the nerve ending but also from glial cells and muscle fiber; (v) molecular mechanisms of the regulation of synaptic transmission are highly diverse and go beyond the alteration of the number of the released acetylcholine quanta. Thus, the neuromuscular junction shall be deemed currently as complicated and adaptive synapse characterized by a wide range of multiloop intercellular signaling pathways between presynaptic motor neuron ending, muscle fiber, and glial cells ensuring a high safety factor of synaptic transmission and the possibility of its fine tuning.

Treatment of chronic pruritus-what is new?

Chronic pruritus is one of the most common and stressful symptoms in medicine. Therapy remains agreat challenge because of the lack of approved therapies. In the recent past agreater understanding of the pathogenesis has enabled the results to be translated into new forms of therapy. The various therapies target awide range of points in the pruritic cascade-from blockade of intracellular and intercellular signaling pathways in the skin to the modulation of neurotransmission. This article provides asummary of current therapeutic options based on the current S2K guideline and gives an overview about recent developments in antipruritic treatments.

Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload.

The cardiac extracellular matrix is a complex architectural network that serves many functions, including providing structural and biochemical support to surrounding cells and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to the progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of proinflammatory and profibrotic responses induce a vicious cycle, which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix. Furthermore, excess synthesis and activation of the enzyme lysyl oxidase (LOX) during disease increases collagen cross-linking, which significantly increases collagen resistance to degradation by matrix metalloproteinases (MMPs). In the present study, the aortocaval fistula model of volume overload (VO) was used to determine whether LOX inhibition could prevent adverse changes in the ECM and subsequent cardiac dysfunction. The major findings from this study were that LOX inhibition 1) prevented VO-induced increases in left ventricular wall stress; 2) partially attenuated VO-induced ventricular hypertrophy; 3) completely blocked the increases in fibrotic proteins, including collagens, MMPs, and their tissue inhibitors; and 4) prevented the VO-induced decline in cardiac function. It remains unclear whether a direct interaction between LOX and MMPs exists; however, our experiments suggest a potential link between the two because LOX inhibition completely attenuated VO-induced increases in MMPs. Overall, our study demonstrated key cardioprotective effects of LOX inhibition against adverse cardiac remodeling due to chronic VO. NEW & NOTEWORTHY Although the primary role of lysyl oxidase (LOX) is to cross-link collagens, we found that elevated LOX during cardiac disease plays a key role in the progression of heart failure. Here, we show that inhibition of LOX in volume-overloaded rats prevented the development of cardiac dysfunction and improved ventricular collagen and matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles.

Hippo Signaling Circuit and Divergent Tissue Growth in Mammalian Eye.

Vertebrate organ development is accompanied by demarcation of tissue compartments, which grow coordinately with their neighbors. Hence, perturbing the coordinative growth of neighboring tissue compartments frequently results in organ malformation. The growth of tissue compartments is regulated by multiple intercellular and intracellular signaling pathways, including the Hippo signaling pathway that limits the growth of various organs. In the optic neuroepithelial continuum, which is partitioned into the retina, retinal pigment epithelium (RPE) and ciliary margin (CM) during eye development, the Hippo signaling activity operates differentially, as it does in many tissues. In this review, we summarize recent studies that have explored the relationship between the Hippo signaling pathway and growth of optic neuroepithelial compartments. We will focus particularly on the roles of a tumor suppressor, neurofibromin 2 (NF2), whose expression is not only dependent on compartment-specific transcription factors, but is also subject to regulation by a Hippo-Yap feedback signaling circuit.