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Regulation of extracellular matrix organization by BMP signaling in Caenorhabditis elegans.

ABSTRACT: In mammals, Bone Morphogenetic Protein (BMP) pathway signaling is important for the growth and homeostasis of extracellular matrix, including basement membrane remodeling, scarring, and bone growth. A conserved BMP member in Caenorhabditis elegans, DBL-1, regulates body length in a dose-sensitive manner. Loss of DBL-1 pathway signaling also results in increased anesthetic sensitivity. However, the physiological basis of these pleiotropic phenotypes is largely unknown. We created a DBL-1 over-expressing strain and show that sensitivity to anesthetics is inversely related to the dose of DBL-1. Using pharmacological, genetic analyses, and a novel dye permeability assay for live, microwave-treated animals, we confirm that DBL-1 is required for the barrier function of the cuticle, a specialized extracellular matrix. We show that DBL-1 signaling is required to prevent animals from forming tail-entangled aggregates in liquid. Stripping lipids off the surface of wild-type animals recapitulates this phenotype. Finally, we find that DBL-1 signaling affects ultrastructure of the nematode cuticle in a dose-dependent manner, as surface lipid content and cuticular organization are disrupted in animals with genetically altered DBL-1 levels. We propose that the lipid layer coating the nematode cuticle normally prevents tail entanglement, and that reduction of this layer by loss of DBL-1 signaling promotes aggregation. This work provides a physiological mechanism that unites the DBL-1 signaling pathway roles of not only body size regulation and drug responsiveness, but also the novel Hoechst 33342 staining and aggregation phenotypes, through barrier function, content, and organization of the cuticle.

SUBMITTER: Schultz RD

PROVIDER: S-EPMC4094471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Correction: Regulation of Extracellular Matrix Organization by BMP Signaling in Caenorhabditis elegans.

Project description:[This corrects the article DOI: 10.1371/journal.pone.0101929.].

| S-EPMC4312017 | biostudies-literature

Feedback regulation of BMP signaling by Caenorhabditis elegans cuticle collagens.

Project description:Cellular responsiveness to environment, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway contributing to this responsiveness is the BMP signaling pathway. Owing to their broad and potent functions, BMPs and their pathways are regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a regulator of body size. We previously showed that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We now identify feedback regulation of DBL-1/BMP through analysis of four DBL-1-regulated collagen genes. Inactivation of any of these genes reduces DBL-1/BMP signaling, measured by a pathway activity reporter. Furthermore, depletion of these collagens reduces GFP::DBL-1 fluorescence and acts unexpectedly at the level of dbl-1 transcription. We conclude that cuticle, a specialized ECM, impinges on DBL-1/BMP expression and signaling. Interestingly, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact independent due to physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel regulatory mechanism for BMP signaling, with broader implications for mechanical regulation of gene expression.

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Lipocalins Are Required for Apical Extracellular Matrix Organization and Remodeling in Caenorhabditis elegans.

Project description:A lipid and glycoprotein-rich apical extracellular matrix (aECM) or glycocalyx lines exposed membranes in the body, and is particularly important to protect narrow tube integrity. Lipocalins ("fat cups") are small, secreted, cup-shaped proteins that bind and transport lipophilic cargo and are often found in luminal or aECM compartments such as mammalian plasma, urine, or tear film. Although some lipocalins can bind known aECM lipids and/or matrix metalloproteinases, it is not known if and how lipocalins affect aECM structure due to challenges in visualizing the aECM in most systems. Here we show that two Caenorhabditiselegans lipocalins, LPR-1 and LPR-3, have distinct functions in the precuticular glycocalyx of developing external epithelia. LPR-1 moves freely through luminal compartments, while LPR-3 stably localizes to a central layer of the membrane-anchored glycocalyx, adjacent to the transient zona pellucida domain protein LET-653 Like LET-653 and other C. elegans glycocalyx components, these lipocalins are required to maintain the patency of the narrow excretory duct tube, and also affect multiple aspects of later cuticle organization. lpr-1 mutants cannot maintain a continuous excretory duct apical domain and have misshapen cuticle ridges (alae) and abnormal patterns of cuticular surface lipid staining. lpr-3 mutants cannot maintain a passable excretory duct lumen, properly degrade the eggshell, or shed old cuticle during molting, and they lack cuticle barrier function. Based on these phenotypes, we infer that both LPR-1 and LPR-3 are required to build a properly organized aECM, while LPR-3 additionally is needed for aECM clearance and remodeling. The C. elegans glycocalyx provides a powerful system, amenable to both genetic analysis and live imaging, for investigating how lipocalins and lipids affect aECM structure.

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Extracellular matrix regulation of stress response genes during larval development in Caenorhabditis elegans.

Project description:Mutation or loss of 6 extracellular matrix collagen genes disrupts annular furrows in adult C. elegans cuticles, causes a wide "Dumpy" body morphology, and activates osmotic, detoxification, and antimicrobial defense genes. High environmental osmolarity reduces internal turgor pressure, physically distorts the epidermis, and activates the same stress responses. Collagen gene mutations that cause Dumpy without furrow disruption do not activate stress responses. These results are consistent with an extracellular damage sensor associated with furrows in the adult cuticle that regulates environmental stress responses in adjacent cells. Several cuticle characteristics change between molts, but all stages have annular furrows and express furrow collagen genes. We compared body shape, furrow organization imaged with differential interference contrast microscopy, and stress response gene expression in furrow collagen gene mutants at all postembryonic stages. We find that most body shape and furrow disorganization phenotypes start at the L3 stage and increase in severity with each molt afterwards. Stress response genes were induced the strongest in adults, correlating with the greatest Dumpy and furrow phenotypes. Although weaker than in adults, osmolyte transporter gene hmit-1.1 and antimicrobial gene nlp-29 were also induced in some early larvae that had weak or undetectable cuticle phenotypes. Our data are consistent with progressive cuticle phenotypes in which each new cuticle is at least partially directed by organization of the former cuticle. Gene expression and cuticle data support the role of furrow disruption as a signal in L4 larvae and adults, but also suggest a role for other cuticle organization or epidermal cell effects in early larvae.

| S-EPMC9635657 | biostudies-literature

BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans.

Project description:Body size is a tightly regulated phenotype in metazoans that depends on both intrinsic and extrinsic factors. While signaling pathways are known to control organ and body size, the downstream effectors that mediate their effects remain poorly understood. In the nematode Caenorhabditis elegans, a Bone Morphogenetic Protein (BMP)-related signaling pathway is the major regulator of growth and body size. We investigated the transcriptional network through which the BMP pathway regulates body size and identified cuticle collagen genes as major effectors of growth control. We demonstrate that cuticle collagens can act as positive regulators (col-41), negative regulators (col-141), or dose-sensitive regulators (rol-6) of body size. Moreover, we find a requirement of BMP signaling for stage-specific expression of cuticle collagen genes. We show that the Smad signal transducers directly bind conserved Smad-binding elements in regulatory regions of col-141 and col-142, but not of col-41 Hence, cuticle collagen genes may be directly and indirectly regulated via the BMP pathway. Our work thus connects a conserved signaling pathway with its critical downstream effectors, advancing insight into how body size is specified. Since collagen mutations and misregulation are implicated in numerous human genetic disorders and injury sequelae, understanding how collagen gene expression is regulated has broad implications.

| S-EPMC6283163 | biostudies-literature

Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling.

Project description:Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL-1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.

| S-EPMC5765361 | biostudies-literature

An extracellular matrix protein promotes anillin-dependent processes in the Caenorhabditis elegans germline.

Project description:Cell division requires constriction of an actomyosin ring to segregate the genetic material equally into two daughter cells. The spatial and temporal regulation of the contractile ring at the division plane primarily depends on intracellular signals mediated by the centralspindlin complex and astral microtubules. Although much investigative work has elucidated intracellular factors and mechanisms controlling this process, the extracellular regulation of cytokinesis remains unclear. Thus far, the extracellular matrix protein Hemicentin (HIM-4) has been proposed to be required for cleavage furrow stabilization. The underlying molecular mechanism, however, has remained largely unknown. Here, we show that HIM-4 and anillin (ANI-1) genetically act in the same pathway to maintain the rachis bridge stability in the germline. Our FRAP experiments further reveal that HIM-4 restricts the motility of ANI-1. In addition, we demonstrate that HIM-4 is recruited to the cleavage site in dividing germ cells and promotes the proper ingression of the cleavage membrane. Collectively, we propose that HIM-4 is an extracellular factor that regulates ANI-1 for germ cell membrane stabilization and contractile ring formation in Caenorhabditis elegans germline cells.

| S-EPMC6467243 | biostudies-literature

The RGM protein DRAG-1 positively regulates a BMP-like signaling pathway in Caenorhabditis elegans.

Project description:The bone morphogenetic protein (BMP) signaling pathway regulates multiple developmental and homeostatic processes. Mutations in the pathway can cause a variety of somatic and hereditary disorders in humans. Multiple levels of regulation, including extracellular regulation, ensure proper spatiotemporal control of BMP signaling in the right cellular context. We have identified a modulator of the BMP-like Sma/Mab pathway in C. elegans called DRAG-1. DRAG-1 is the sole member of the repulsive guidance molecule (RGM) family of proteins in C. elegans, and is crucial in regulating body size and mesoderm development. Using a combination of molecular genetic and biochemical analyses, we demonstrate that DRAG-1 is a membrane-associated protein that functions at the ligand-receptor level to modulate the Sma/Mab pathway in a cell-type-specific manner. We further show that DRAG-1 positively modulates this BMP-like pathway by using a novel Sma/Mab-responsive reporter. Our work provides a direct link between RGM proteins and BMP signaling in vivo and a simple and genetically tractable system for mechanistic studies of RGM protein regulation of BMP pathways.

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2020-08-05 | GSE146973 | GEO

Two sets of interacting collagens form functionally distinct substructures within a Caenorhabditis elegans extracellular matrix.

Project description:A ubiquitous feature of collagens is protein interaction, the trimerization of monomers to form a triple helix followed by higher order interactions during the formation of the mature extracellular matrix. The Caenorhabditis elegans cuticle is a complex extracellular matrix consisting predominantly of cuticle collagens, which are encoded by a family of approximately 154 genes. We identify two discrete interacting sets of collagens and show that they form functionally distinct matrix substructures. We show that mutation in or RNA-mediated interference of a gene encoding a collagen belonging to one interacting set affects the assembly of other members of that set, but not those belonging to the other set. During cuticle synthesis, the collagen genes are expressed in a distinct temporal series, which we hypothesize exists to facilitate partner finding and the formation of appropriate interactions between encoded collagens. Consistent with this hypothesis, we find for the two identified interacting sets that the individual members of each set are temporally coexpressed, whereas the two sets are expressed approximately 2 h apart during matrix synthesis.

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