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Logical versus kinetic modeling of biological networks: applications in cancer research

Abstract: Publication date: September 2018 Source:Current Opinion in Chemical Engineering, Volume 21 Author(s): Laurence Calzone, Emmanuel Barillot, Andrei Zinovyev Mathematical modeling of biological networks is a promising approach to understand the complexity of cancer progression, which can be understood as accumulated abnormalities in the kinetics of cellular biochemistry. Two major modeling formalisms (languages) have been used for this purpose in the last couple of decades: one is based on the application of classical chemical kinetics of reaction networks and the other one is based on discrete kinetics representation (called logical formalism for simplicity here), governed by logical state update rules. In this short review, we remind the reader how these two methodologies complement each other but also present the fast and recent development of semi-quantitative approaches for modeling large biological networks, with a spectrum of complementary ideas each inheriting and combining features of both modeling formalisms. We also notice an increasing influence of the recent success of machine learning and artificial intelligence onto the methodology of mathematical network modeling in cancer research, leading to appearance of a number of pragmatic hybrid approaches. To illustrate the two approaches, logical versus kinetic modeling, we provide an example describing the same biological process with different description granularity in both discrete and continuous formalisms. The model focuses on a central question in cancer biology: understanding the mechanisms of metastasis appearance. We conclude that despite significant progress in development of modeling ideas, predicting response of large biological networks involved in cancer to various perturbations remains a major unsolved challenge in cancer systems biology. Graphical abstract

Pub.: 15 Apr '18, Pinned: 26 Apr '18

Protein Acylation Affects the Artificial Biosynthetic Pathway for Pinosylvin Production in Engineered E. coli

Abstract: The effect of regulatory system on the engineered biosynthetic pathway in chassis cells remains incompletely understood in microorganisms. Acyl-CoAs function as key precursors for the biosynthesis of various natural products and the dominant donors for protein acylation. The polyphenol pinosylvin, with high antimicrobial and antifungal activities, is biosynthesized with malonyl-CoA as its direct precursors. But correlation between lysine malonylation and pinosylvin biosynthesis remains unknown. Herein, we found that the malonyl-CoA-driven lysine malonylation plays an important role in interaction between the engineered pathway of pinosylvin synthesis and E. coli chassis cell. Oversupply of malonyl-CoA leads to an increase in malonylation level of global proteome as well as the enzymes in the artificial pathway, thereby decreasing yield of pinosylvin. The results revealed that the intricate balance of cellular acyl-CoA concentrations is critical for the yields of acyl-CoA-derived natural products. We next modified the enzymes in the biosynthetic pathway to adjust their acylation level and successfully improved the yield of pinosylvin. Our study uncovers the effect of protein acylation on the biosynthetic pathway, helps optimization of synthetic constructs, and provides new strategies in metabolic engineering and synthetic biology at the protein post-translational level.

Pub.: 25 Apr '18, Pinned: 26 Apr '18

The past and presence of gene targeting: from chemicals and DNA via proteins to RNA.

Abstract: The ability to target DNA specifically at any given position within the genome allows many intriguing possibilities and has inspired scientists for decades. Early gene-targeting efforts exploited chemicals or DNA oligonucleotides to interfere with the DNA at a given location in order to inactivate a gene or to correct mutations. We here describe an example towards correcting a genetic mutation underlying Pompe's disease using a nucleotide-fused nuclease (TFO-MunI). In addition to the promise of gene correction, scientists soon realized that genes could be inactivated or even re-activated without inducing potentially harmful DNA damage by targeting transcriptional modulators to a particular gene. However, it proved difficult to fuse protein effector domains to the first generation of programmable DNA-binding agents. The engineering of gene-targeting proteins (zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs)) circumvented this problem. The disadvantage of protein-based gene targeting is that a fusion protein needs to be engineered for every locus. The recent introduction of CRISPR/Cas offers a flexible approach to target a (fusion) protein to the locus of interest using cheap designer RNA molecules. Many research groups now exploit this platform and the first human clinical trials have been initiated: CRISPR/Cas has kicked off a new era of gene targeting and is revolutionizing biomedical sciences.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'. © 2018 The Author(s).

Pub.: 25 Apr '18, Pinned: 26 Apr '18

Selective recognition of N 4-methylcytosine in DNA by engineered transcription-activator-like effectors.

Abstract: The epigenetic DNA nucleobases 5-methylcytosine (5mC) and 4-methylcytosine (4mC) coexist in bacterial genomes and have important functions in host defence and transcription regulation. To better understand the individual biological roles of both methylated nucleobases, analytical strategies for distinguishing unmodified cytosine (C) from 4mC and 5mC are required. Transcription-activator-like effectors (TALEs) are programmable DNA-binding repeat proteins, which can be re-engineered for the direct detection of epigenetic nucleobases in user-defined DNA sequences. We here report the natural, cytosine-binding TALE repeat to not strongly differentiate between 5mC and 4mC. To engineer repeats with selectivity in the context of C, 5mC and 4mC, we developed a homogeneous fluorescence assay and screened a library of size-reduced TALE repeats for binding to all three nucleobases. This provided insights into the requirements of size-reduced TALE repeats for 4mC binding and revealed a single mutant repeat as a selective binder of 4mC. Employment of a TALE with this repeat in affinity enrichment enabled the isolation of a user-defined DNA sequence containing a single 4mC but not C or 5mC from the background of a bacterial genome. Comparative enrichments with TALEs bearing this or the natural C-binding repeat provides an approach for the complete, programmable decoding of all cytosine nucleobases found in bacterial genomes.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'. © 2018 The Author(s).

Pub.: 25 Apr '18, Pinned: 26 Apr '18

Desferrioxamine biosynthesis: diverse hydroxamate assembly by substrate-tolerant acyl transferase DesC.

Abstract: Hydroxamate groups play key roles in the biological function of diverse natural products. Important examples include trichostatin A, which inhibits histone deacetylases via coordination of the active site zinc(II) ion with a hydroxamate group, and the desferrioxamines, which use three hydroxamate groups to chelate ferric iron. Desferrioxamine biosynthesis in species involves the DesD-catalysed condensation of various -acylated derivatives of -hydroxycadaverine with two molecules of -succinyl--hydroxycadaverine to form a range of linear and macrocyclic tris-hydroxamates. However, the mechanism for assembly of the various -acyl--hydroxycadaverine substrates of DesD from -hydroxycadaverine has until now been unclear. Here we show that the gene of encodes the acyl transferase responsible for this process. DesC catalyses the -acylation of -hydroxycadaverine with acetyl, succinyl and myristoyl-CoA, accounting for the diverse array of desferrioxamines produced by The X-ray crystal structure of DesE, the ferrioxamine lipoprotein receptor, in complex with ferrioxamine B (which is derived from two units of -succinyl--hydroxycadaverine and one of -acetyl--hydroxycadaverine) was also determined. This showed that the acetyl group of ferrioxamine B is solvent exposed, suggesting that the corresponding acyl group in longer chain congeners can protrude from the binding pocket, providing insights into their likely function. This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'. © 2018 The Author(s).

Pub.: 25 Apr '18, Pinned: 26 Apr '18

Interplay between long non-coding RNAs and epigenetic machinery: emerging targets in cancer?

Abstract: Of the diverse array of putative molecular and biological functions assigned to long non-coding RNAs (lncRNAs), one attractive perspective in epigenetic research has been the hypothesis that lncRNAs directly interact with the proteins involved in the modulation of chromatin conformation. Indeed, epigenetic modifiers are among the most frequent protein partners of lncRNAs that have been identified to date, of which histone methyltransferases and protein members of the Polycomb Repressive Complex PRC2 have received considerable attention. This review is focused on how lncRNAs interface with epigenetic factors to shape the outcomes of crucial biological processes such as regulation of gene transcription, modulation of nuclear architecture, X inactivation in females and pre-mRNA splicing. Because of our increasing knowledge of their role in development and cellular differentiation, more research is beginning to be done into the deregulation of lncRNAs in human disorders. Focusing on cancer, we describe some key examples of disease-focused lncRNA studies. This knowledge has significantly contributed to our ever-improving understanding of how lncRNAs interact with epigenetic factors of human disease, and has also provided a plethora of much-needed novel prognostic biomarker candidates or potential therapeutic targets. Finally, current limitations and perspectives on lncRNA research are discussed here.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'. © 2018 The Authors.

Pub.: 25 Apr '18, Pinned: 26 Apr '18

Psychosocial Stress Exposure Disrupts Mammary Gland Development

Abstract: Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8–25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.

Pub.: 23 Apr '18, Pinned: 26 Apr '18

Relationship between the Flavonoid Composition and Flower Color Variation in Victoria.

Abstract: Victoria (Nymphaeaceae), an annual or perennial aquatic plant genus, contains only two species: V. amazonica (Poepp.) J. C. Sowerby and V. cruziana A. D. Orb. Both species exhibit large floating leaves and variable flower color. Both Victoria are night bloomers, which have white petals on the first blooming night, which then turn pink or ruby red on the second blooming day. The mechanism of the color change of Victoria petals during anthesis is still unclear. In this study, flavonoids in Victoria petals of both species were evaluated and quantified by high-performance liquid chromatography with photodiode array detection (HPLC-DAD) and by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) for the first time. In total, fourteen flavonoids were detected in Victoria petals, including four anthocyanins and ten flavonols. The flavonoid compositions differed across the two species, resulting in different colors between the inner and outer petals. With increased anthocyanin content across blooming days, the color of Victoria flowers changed over time. The results of this study will improve understanding of the chemical mechanism of color formation and lay the foundation for selective color breeding in Victoria. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Pub.: 24 Apr '18, Pinned: 26 Apr '18

Effects of increasing hydrophobicity by N-terminal myristoylation on the antibacterial and hemolytic activities of the C-terminal cationic segments of human-β-defensins 1-3.

Abstract: Analogs of the cationic C-terminal segments of human-β-defensins HBD1-3, Phd1-3 with a single disulfide bond, exhibited comparable antimicrobial activity that were salt sensitive. They did not show hemolytic activity. In the present study, N-terminal myristoylation was carried out on Phd1-3 to examine whether increasing hydrophobicity would result in improved antibacterial activity. The antibacterial activity of the oxidized myristoylated peptides MPhd1-3 and their reduced forms MPhd1r-3r was determined. These peptides showed enhanced antibacterial activity as compared to Phd1-3, on mid-log phase and stationary phase of Staphylococcus aureus and Escherichia coli, except MPhd1r-3r that were inactive on stationary phase E. coli. In the presence of 150 mM NaCl, MPhd1-3 showed activity against S. aureus. MPhd1and 2 exhibited activity against E. coli but MPhd3 was inactive. Zeta potential measurements indicated that MPhd1-3 were more effective in surface charge neutralization of bacteria as compared to Phd1-3. MPhd1-3 exhibited hemolytic activity to varying extents with MPhd1 being most hemolytic. The data indicate that myristoylation enhances antibacterial activity and modulates hemolytic activity to different extents. Apart from hydrophobicity, distribution of cationic residues in MPhd1-3 plays important roles for these activities. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Pub.: 24 Apr '18, Pinned: 26 Apr '18

Frontiers of Complex Disease Mechanisms: Membrane Surface Tension May Link Genotype to Phenotype in Glaucoma.

Abstract: Although many monogenic diseases are understood based upon structural changes of gene products, less progress has been made concerning polygenic disease mechanisms. This article presents a new interdisciplinary approach to understand complex diseases, especially their genetic polymorphisms. I focus upon primary open angle glaucoma (POAG). Although elevated intraocular pressure (IOP) and oxidative stress are glaucoma hallmarks, the linkages between these factors and cell death are obscure. Reactive oxygen species (ROS) promote the formation of oxidatively truncated phosphoglycerides (OTP), free fatty acids, lysophosphoglycerides, oxysterols, and other chemical species that promote membrane disruption and decrease membrane surface tension. Several POAG-linked gene polymorphisms identify proteins that manage damaged lipids and/or influence membrane surface tension. POAG-related genes expected to participate in these processes include: , and . POAG-related gene products are expected to influence membrane surface tension, strength, and repair. I propose that heightened IOP overcomes retinal ganglion cell (RGC) membrane compressive strength, weakened by damaged lipid accumulation, to form pores. The ensuing structural failure promotes apoptosis and blindness. The linkage between glaucoma genotype and phenotype is mediated by physical events. Force balancing between the IOP and compressive strength regulates pore nucleation; force balancing between pore line tension and membrane surface tension regulates pore growth. Similar events may contribute to traumatic brain injury, Alzheimer's disease, and macular degeneration.

Pub.: 24 Apr '18, Pinned: 26 Apr '18

Anatomy of triply-periodic network assemblies: characterizing skeletal and inter-domain surface geometry of block copolymer gyroids.

Abstract: Triply-periodic networks (TPNs), like the well-known gyroid and diamond network phases, abound in soft matter assemblies, from block copolymers (BCPs), lyotropic liquid crystals and surfactants to functional architectures in biology. While TPNs are, in reality, volume-filling patterns of spatially-varying molecular composition, physical and structural models most often reduce their structure to lower-dimensional geometric objects: the 2D interfaces between chemical domains; and the 1D skeletons that thread through inter-connected, tubular domains. These lower-dimensional structures provide a useful basis of comparison to idealized geometries based on triply-periodic minimal, or constant-mean curvature surfaces, and shed important light on the spatially heterogeneous packing of molecular constituents that form the networks. Here, we propose a simple, efficient and flexible method to extract a 1D skeleton from 3D volume composition data of self-assembled networks. We apply this method to both self-consistent field theory predictions as well as experimental electron microtomography reconstructions of the double-gyroid phase of an ABA triblock copolymer. We further demonstrate how the analysis of 1D skeleton, 2D inter-domain surfaces, and combinations therefore, provide physical and structural insight into TPNs, across multiple length scales. Specifically, we propose and compare simple measures of network chirality as well as domain thickness, and analyze their spatial and statistical distributions in both ideal (theoretical) and non-ideal (experimental) double gyroid assemblies.

Pub.: 24 Apr '18, Pinned: 26 Apr '18

Molecular description of α-keto-based inhibitors of cruzain with activity against Chagas disease combining 3D-QSAR studies and molecular dynamics.

Abstract: In this work a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q and r ) for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR-3D study. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Pub.: 24 Apr '18, Pinned: 26 Apr '18

Identification and validation nucleolin as a target of curcumol in nasopharyngeal carcinoma cells.

Abstract: Identification of the specific protein target(s) of a drug is a critical step in unraveling its mechanisms of action (MOA) in many natural products. Curcumol, isolated from well known Chinese medicinal plant Curcuma zedoary, has been shown to possess multiple biological activities. It can inhibit nasopharyngeal carcinoma (NPC) proliferation and induce apoptosis, but its target protein(s) in NPC cells remains unclear. In this study, we employed a mass spectrometry-based chemical proteomics approach reveal the possible protein targets of curcumol in NPC cells. Cellular thermal shift assay (CETSA), molecular docking and cell-based assay was used to validate the binding interactions. Chemical proteomics capturing uncovered that NCL is a target of curcumol in NPC cells, Molecular docking showed that curcumol bound to NCL with an -7.8 kcal/mol binding free energy. Cell function analysis found that curcumol's treatment leads to a degradation of NCL in NPC cells, and it showed slight effects on NP69 cells. In conclusion, our results providing evidences that NCL is a target protein of curcumol. We revealed that the anti-cancer effects of curcumol in NPC cells are mediated, at least in part, by NCL inhibition. Many natural products showed high bioactivity, while their mechanisms of action (MOA) are very poor or completely missed. Understanding the MOA of natural drugs can thoroughly exploit their therapeutic potential and minimize their adverse side effects. Identification of the specific protein target(s) of a drug is a critical step in unraveling its MOA. Compound-centric chemical proteomics is a classic chemical proteomics approach which integrates chemical synthesis with cell biology and mass spectrometry (MS) to identify protein targets of natural products determine the drug mechanism of action, describe its toxicity, and figure out the possible cause of off-target. It is an affinity-based chemical proteomics method to identify small molecule-protein interactions through affinity chromatography approach coupled with mass spectrometry, has been conventionally used to identify target proteins and has yielded good results. Curcumol, has shown effective inhibition on Nasopharyngeal Carcinoma (NPC) Cells, interacted with NCL and then initiated the anti-tumor biological effect. This research demonstrated the effectiveness of chemical proteomics approaches in natural drugs molecular target identification, revealing and understanding of the novel mechanism of actions of curcumol is crucial for cancer prevention and treatment in nasopharynx cancer. Copyright © 2017. Published by Elsevier B.V.

Pub.: 24 Apr '18, Pinned: 26 Apr '18

Glycan Chains of Gangliosides: Functional Ligands for Tissue Lectins (Siglecs/Galectins)

Abstract: Publication date: Available online 28 March 2018 Source:Progress in Molecular Biology and Translational Science Author(s): R.W. Ledeen, J. Kopitz, J. Abad-Rodríguez, H.-J. Gabius Molecular signals on the cell surface are responsible for adhesion and communication. Of relevance in this respect, their chemical properties endow carbohydrates with the capacity to store a maximum of information in a minimum of space. One way to present glycans on the cell surface is their covalent conjugation to a ceramide anchor. Among the resulting glycosphingolipids, gangliosides are special due to the presence of at least one sialic acid in the glycan chains. Their spatial accessibility and the dynamic regulation of their profile are factors that argue in favor of a role of glycans of gangliosides as ligands (counterreceptors) for carbohydrate-binding proteins (lectins). Indeed, as discovered first for a bacterial toxin, tissue lectins bind gangliosides and mediate contact formation (trans) and signaling (cis). While siglecs have a preference for higher sialylated glycans, certain galectins also target the monosialylated pentasaccharide of ganglioside GM1. Enzymatic interconversion of ganglioside glycans by sialidase action, relevant for neuroblastoma cell differentiation and growth control in vitro, for axonogenesis and axon regeneration, as well as for proper communication between effector and regulatory T cells, changes lectin-binding affinity profoundly. The GD1a-to-GM1 “editing” is recognized by such lectins, for example, myelin-associated glycoprotein (siglec-4) losing affinity and galectin-1 gaining reactivity, and then translated into postbinding signaling. Orchestrations of loss/gain of affinity, of ganglioside/lectin expression, and of lectin presence in a network offer ample opportunities for fine-tuning. Thus glycans of gangliosides such as GD1a and GM1 are functional counterreceptors by a pairing with tissue lectins, an emerging aspect of ganglioside and lectin functionality.

Pub.: 15 Apr '18, Pinned: 26 Apr '18

Soil organic matter quality exerts a stronger control than stoichiometry on microbial substrate use efficiency along a latitudinal transect

Abstract: Publication date: June 2018 Source:Soil Biology and Biochemistry, Volume 121 Author(s): Mounir Takriti, Birgit Wild, Jörg Schnecker, Maria Mooshammer, Anna Knoltsch, Nikolay Lashchinskiy, Ricardo J. Eloy Alves, Norman Gentsch, Antje Gittel, Robert Mikutta, Wolfgang Wanek, Andreas Richter A substantial portion of soil organic matter (SOM) is of microbial origin. The efficiency with which soil microorganisms can convert their substrate carbon (C) into biomass, compared to how much is lost as respiration, thus co-determines the carbon storage potential of soils. Despite increasing insight into soil microbial C cycling, empirical measurements of microbial C processing across biomes and across soil horizons remain sparse. The theory of ecological stoichiometry predicts that microbial carbon use efficiency (CUE), i.e. growth over uptake of organic C, strongly depends on the relative availability of C and nutrients, particularly N, as microorganisms will either respire excess C or conserve C while mineralising excess nutrients. Microbial CUE is thus expected to increase from high to low latitudes and from topsoil to subsoil as the soil C:N and the stoichiometric imbalance between SOM and the microbial biomass decrease. To test these hypotheses, we collected soil samples from the organic topsoil, mineral topsoil, and mineral subsoil of seven sites along a 1500-km latitudinal transect in Western Siberia. As a proxy for CUE, we measured the microbial substrate use efficiency (SUE) of added substrates by incubating soil samples with a mixture of 13C labelled sugars, amino sugars, amino acids, and organic acids and tracing 13C into microbial biomass and released CO2. In addition to soil and microbial C:N stoichiometry, we also determined the potential extracellular enzyme activities of cellobiohydrolase (CBH) and phenol oxidase (POX) and used the CBH:POX ratio as an indicator of SOM substrate quality. We found an overall decrease of SUE with latitude, corresponding to a decrease in mean annual temperature, in mineral soil horizons. SUE decreased with decreasing stoichiometric imbalance in the organic and mineral topsoil, while a relationship of SUE with soil C:N was only found in the mineral topsoil. However, contrary to our hypothesis, SUE did not increase with soil depth and mineral subsoils displayed lower average SUE than mineral topsoils. Both within individual horizons and across all horizons SUE was strongly correlated with CBH:POX ratio as well as with climate variables. Since enzyme activities likely reflect the chemical properties of SOM, our results indicate that SOM quality exerts a stronger control on SUE than SOM stoichiometry, particularly in subsoils were SOM has been turned over repeatedly and there is little variation in SOM elemental ratios.

Pub.: 15 Apr '18, Pinned: 26 Apr '18

The Physical and Biochemical Properties of the Extracellular Matrix Regulate Cell Fate

Abstract: Publication date: Available online 21 March 2018 Source:Current Topics in Developmental Biology Author(s): Jonathon M. Muncie, Valerie M. Weaver The extracellular matrix is a complex network of hydrated macromolecular proteins and sugars that, in concert with bound soluble factors, comprise the acellular stromal microenvironment of tissues. Rather than merely providing structural information to cells, the extracellular matrix plays an instructive role in development and is critical for the maintenance of tissue homeostasis. In this chapter, we review the composition of the extracellular matrix and summarize data illustrating its importance in embryogenesis, tissue-specific development, and stem cell differentiation. We discuss how the biophysical and biochemical properties of the extracellular matrix ligate specific transmembrane receptors to activate intracellular signaling that alter cell shape and cytoskeletal dynamics to modulate cell growth and viability, and direct cell migration and cell fate. We present examples describing how the extracellular matrix functions as a highly complex physical and chemical entity that regulates tissue organization and cell behavior through a dynamic and reciprocal dialogue with the cellular constituents of the tissue. We suggest that the extracellular matrix not only transmits cellular and tissue-level force to shape development and tune cellular activities that are key for coordinated tissue behavior, but that it is itself remodeled such that it temporally evolves to maintain the integrated function of the tissue. Accordingly, we argue that perturbations in extracellular matrix composition and structure compromise key developmental events and tissue homeostasis, and promote disease.

Pub.: 19 Apr '18, Pinned: 26 Apr '18