scholarly journals Extracellular matrix regulates morphogenesis and function of ciliated sensory organs in Caenorhabditis elegans

2018 ◽  
Author(s):  
Deanna M. De Vore ◽  
Karla M. Knobel ◽  
Ken C.Q. Nguyen ◽  
David H. Hall ◽  
Maureen M. Barr
Keyword(s):  
Extracellular Matrix ◽  
Dendritic Morphology ◽  
C Elegans ◽  
Genes Encoding ◽  
Health And Disease ◽  
Autosomal Dominant Polycystic Kidney ◽  
Signaling Organelles ◽  
And Function

ABSTRACTCilia and extracellular vesicles (EVs) are signaling organelles that play important roles in human health and disease. In C. elegans and mammals, the Autosomal Dominant Polycystic Kidney Disease (ADPKD) gene products polycystin-1 and polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation. Hence, the nematode offers an excellent system in which to address central questions regarding the biology of cilia, EVs, and the polycystins. We discovered an unexpected role of the mec-1, mec-5, and mec-9 genes encoding extracellular matrix (ECM) components. We determined that these ECM encoding genes regulate polycystin localization and function, ciliary EV release, cilia length, dendritic morphology, and neuron-glia interactions. Abnormal ECM and fibrosis are observed in ciliopathies such as ADPKD, nephronophthisis, and Bardet-Biedl Syndrome. Our studies reveal multifaceted roles for ECM proteins in the ciliated nervous system of the worm and provide a powerful new in vivo model to study the relationship between ECM, the polycystins, and ciliopathies.

The extracellular matrix of the developing cornea: diversity, deposition and function*

Development ◽  
1988 ◽  
Vol 103 (Supplement) ◽  
pp. 195-205
Author(s):  
J. B. L. Bard ◽  
M. K. Bansal ◽  
A. S. A. Ross
Keyword(s):  
Extracellular Matrix ◽  
Chondroitin Sulphate ◽  
Corneal Stroma ◽  
Experimental System ◽  
Collagen I ◽  
And Function ◽  
20 Nm

This paper examines the role of the extracellular matrix (ECM) in the development of the cornea. After a brief summary of the corneal structure and ECM, we describe evidence suggesting that the differentiation of neural crest (NC) cells into endothelium and fibroblasts is under the control of ocular ECM. We then examine the role of collagen I in stromal morphogenesis by comparing normal corneas with those of homozygous Movl3 mice which do not make collagen I. We report that, in spite of this absence, the cellular morphology of the Movl3 eye is indistinguishable from that of the wild type. In the 16-day mutant stroma, however, the remaining collagens form small amounts of disorganized, thin fibrils rather than orthogonally organized 20 nm-diameter fibrils; a result implying that collagen I plays only a structural role and that its absence is not compensated for. It also suggests that, because these remaining collagens will not form the normal fibrils that they will in vitro, fibrillogenesis in the corneal stroma differs from that elsewhere. The latter part of the paper describes our current work on chick stromal deposition using corneal epithelia isolated with an intact basal lamina that lay down in vitro ∼3μm-thick stromas of organized fibrils similar to that seen in vivo. This experimental system has yielded two unexpected results. First, the amount of collagen and proteoglycans produced by such epithelia is not dependent on whether its substratum is collagenous and we therefore conclude that stromal production by the intact epithelium is more autonomous than hitherto thought. Second, chondroitin sulphate (CS), the predominant proteoglycan, appears to play no role in stromal morphogenesis: epithelia cultured in testicular hyaluronidase, which degrades CS, lay down stromas whose organization and fibrildiameter distribution are indistinguishable from controls. One possible role for CS, however, is as a lubricant which facilitates corneal growth: it could allow fibrils to move over one another without deforming their orthogonal organization. Finally, we have examined the processes of fibrillogenesis in the corneal stroma and conclude that they are different from those elsewhere in the embryo and in vitro, perhaps because there is in the primary stroma an unidentified, highly hydrated ECM macromolecule that embeds the fibrils and that may mediate their morphogenesis.

scholarly journals Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

2002 ◽  
Vol 13 (3) ◽  
pp. 238-275 ◽  
Author(s):  
D.P. Dickinson
Keyword(s):  
Extracellular Matrix ◽  
Oral Cavity ◽  
Cell Function ◽  
Human Saliva ◽  
Protective Function ◽  
Cysteine Peptidases ◽  
Genes Encoding ◽  
Foreign Proteins ◽  
Health And Disease

Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily “housekeeping” functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefèvre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.

scholarly journals Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lianna Schwartz-Orbach ◽  
Chenzhen Zhang ◽  
Simone Sidoli ◽  
Richa Amin ◽  
Diljeet Kaur ◽  
...  
Keyword(s):  
Chromatin Modification ◽  
Epigenetic Inheritance ◽  
Rnai Pathway ◽  
C Elegans ◽  
And Function ◽  
Nuclear Rnai ◽  
Factor Set

Nuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histonemodifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans. In addition, dsRNA-induced H3K23me3 can persist for multiple generations after the dsRNA exposure has stopped. We demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro. Both set-32 and the germline nuclear RNAi Argonaute, hrde-1, are required for nuclear RNAi-induced H3K23me3 in vivo. Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

scholarly journals Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission and Map2k7 expression in GABAergic interneurons

2021 ◽  
Author(s):  
Jingli Cao ◽  
Weiwei Xian ◽  
Maierdan Palihati ◽  
Yu Zhu ◽  
Guoxiang Wang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Dendritic Morphology ◽  
Gabaergic Interneurons ◽  
Related Gene ◽  
Inhibitory Neurotransmission ◽  
Whole Cell Patch Clamp ◽  
Developmental Niche ◽  
And Function

AbstractIntellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations were mentally retarded. To test its role in development and function of MGE-derived GABAergic interneurons, we performed immunofluorescence staining, whole-cell patch-clamp, MGE transplantation and mRNA-Seq to understand its effect on neuronal differentiation, dendritic morphology, electrophysiology, migration and gene regulation, using mouse MGE-derived GABAergic interneurons infected with AAV-shBrpf1. We found a decreasing trend on parvalbumin+ interneuron differentiation. Moreover, increased firing threshold, decreased number of evoked APs, and a reduced amplitude of mIPSCs were observed before any significant change of MAP2+ dendritic morphology and in vivo migration appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.

scholarly journals Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis

2015 ◽  
Vol 26 (15) ◽  
pp. 2823-2832 ◽  
Author(s):  
Julie E. Maguire ◽  
Malan Silva ◽  
Ken C.Q. Nguyen ◽  
Elizabeth Hellen ◽  
Andrew D. Kern ◽  
...  
Keyword(s):  
Extracellular Vesicle ◽  
Male Mating ◽  
C Elegans ◽  
Vesicle Biogenesis ◽  
Trafficking Defects ◽  
Cilia And Flagella ◽  
Autosomal Dominant Polycystic Kidney ◽  
And Function ◽  
The Relationship

The cilium both releases and binds to extracellular vesicles (EVs). EVs may be used by cells as a form of intercellular communication and mediate a broad range of physiological and pathological processes. The mammalian polycystins (PCs) localize to cilia, as well as to urinary EVs released from renal epithelial cells. PC ciliary trafficking defects may be an underlying cause of autosomal dominant polycystic kidney disease (PKD), and ciliary–EV interactions have been proposed to play a central role in the biology of PKD. In Caenorhabditis elegans and mammals, PC1 and PC2 act in the same genetic pathway, act in a sensory capacity, localize to cilia, and are contained in secreted EVs, suggesting ancient conservation. However, the relationship between cilia and EVs and the mechanisms generating PC-containing EVs remain an enigma. In a forward genetic screen for regulators of C. elegans PKD-2 ciliary localization, we identified CIL-7, a myristoylated protein that regulates EV biogenesis. Loss of CIL-7 results in male mating behavioral defects, excessive accumulation of EVs in the lumen of the cephalic sensory organ, and failure to release PKD-2::GFP-containing EVs to the environment. Fatty acylation, such as myristoylation and palmitoylation, targets proteins to cilia and flagella. The CIL-7 myristoylation motif is essential for CIL-7 function and for targeting CIL-7 to EVs. C. elegans is a powerful model with which to study ciliary EV biogenesis in vivo and identify cis-targeting motifs such as myristoylation that are necessary for EV–cargo association and function.

scholarly journals BIOMARKERS OF CARDIAC FIBROSIS IN ARTERIAL HYPERTENSION

2020 ◽  
Vol 47 (4) ◽  
Author(s):  
N. Ya. Dotsenko ◽  
L. V. Gerasimenko ◽  
S. S. Boev ◽  
I. A. Shekhunova ◽  
A. V. Molodan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Arterial Hypertension ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Structure And Function ◽  
Myocardial Remodeling ◽  
Review Of The Literature ◽  
Health And Disease ◽  
And Function

Abstract The article presents a review of the literature on the role of myocardial fibrosis in the development of myocardial remodeling in patients with arterial hypertension. Information about the state of the structure and function of the extracellular matrix in health and disease is generalized. The characteristics of myocardial fibrosis biomarkers detection in the circulating blood are reflected. Keywords: arterial hypertension, myocardial fibrosis, extracellular matrix, collagen, biomarkers.

scholarly journals Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons

2021 ◽  
Author(s):  
Jingli Cao ◽  
Weiwei Xian ◽  
Maierdan Palihati ◽  
Yu Zhu ◽  
Guoxiang Wang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Dendritic Morphology ◽  
Gabaergic Interneurons ◽  
Related Gene ◽  
Migration Ability ◽  
Inhibitory Neurotransmission ◽  
Whole Cell Patch Clamp ◽  
And Function

Abstract Intellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations showed intellectual disability. To test its role in development and function of MGE-derived GABAergic interneurons, we performed immunofluorescence staining, whole-cell patch-clamp, MGE transplantation and mRNA-Seq to understand its effect on neuronal differentiation, dendritic morphology, electrophysiology, migration and gene regulation, using mouse MGE-derived GABAergic interneurons infected with AAV-shBrpf1. The results showed that Brpf1 knockdown had a decreasing trend, although not significant, on the differentiation of GABAergic interneurons into parvalbumin+ interneurons. Moreover, increased firing threshold, decreased number of evoked action potentials, and a reduced amplitude of miniature inhibitory postsynaptic currents were observed before any significant change of MAP2+ dendritic morphology and in vivo migration ability appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.

scholarly journals Prolyl 4-Hydroxylase Is an Essential Procollagen-Modifying Enzyme Required for Exoskeleton Formation and the Maintenance of Body Shape in the Nematode Caenorhabditis elegans

2000 ◽  
Vol 20 (11) ◽  
pp. 4084-4093 ◽  
Author(s):  
Alan D. Winter ◽  
Antony P. Page
Keyword(s):  
Extracellular Matrix ◽  
Caenorhabditis Elegans ◽  
Collagen Synthesis ◽  
Null Alleles ◽  
Β Subunit ◽  
Α Subunit ◽  
C Elegans ◽  
Link Type ◽  
Genes Encoding

ABSTRACT The multienzyme complex prolyl 4-hydroxylase catalyzes the hydroxylation of proline residues and acts as a chaperone during collagen synthesis in multicellular organisms. The β subunit of this complex is identical to protein disulfide isomerase (PDI). The free-living nematode Caenorhabditis elegans is encased in a collagenous exoskeleton and represents an excellent model for the study of collagen biosynthesis and extracellular matrix formation. In this study, we examined prolyl 4-hydroxylase α-subunit (PHY; EC1.14.11.2 )- and β-subunit (PDI; EC 5.3.4.1 )-encoding genes with respect to their role in collagen modification and formation of theC. elegans exoskeleton. We identified genes encoding two PHYs and a single associated PDI and showed that all three are expressed in collagen-synthesizing ectodermal cells at times of maximal collagen synthesis. Disruption of the pdi gene via RNA interference resulted in embryonic lethality. Similarly, the combinedphy genes are required for embryonic development. Interference with phy-1 resulted in a morphologically dumpy phenotype, which we determined to be identical to the uncharacterizeddpy-18 locus. Two dpy-18 mutant strains were shown to have null alleles for phy-1 and to have a reduced hydroxyproline content in their exoskeleton collagens. This study demonstrates in vivo that this enzyme complex plays a central role in extracellular matrix formation and is essential for normal metazoan development.

Adventitial fibroblasts in vascular structure and function: the role of oxidative stress and beyondThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

2010 ◽  
Vol 88 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Hui Di Wang ◽  
Matthew T. Rätsep ◽  
Alexander Chapman ◽  
Ryan Boyd
Keyword(s):  
Oxidative Stress ◽  
Extracellular Matrix ◽  
Blood Vessel ◽  
Structure And Function ◽  
Vascular Structure ◽  
Matrix Deposition ◽  
Adventitial Fibroblasts ◽  
Health And Disease ◽  
And Function

The vascular adventitia, defined as the area between the external elastic lamina and the outermost edge of the blood vessel, is composed primarily of fibroblasts and for years was thought to be merely a passive structural support for the blood vessel. Consequently, studies pertaining to the role of the adventitia in regulating vascular function have been far outnumbered by those regarding the vascular endothelium. However, recent work has begun to reveal the dynamic properties of the adventitia. It was therefore the aim of this review to provide an overview of the existing knowledge demonstrating the role of the adventitia in regulating vessel structure and function. The main topics covered in this review include the cellular composition of the adventitia and the role of the adventitia in vascular oxidative stress, vasomotor responses, extracellular matrix protein expression, growth factor expression, and endothelin-1 (ET-1) expression. Recent evidence suggests that the adventitia is a major producer of vascular reactive oxygen species. It displays a distinct response to injury, hypoxia, and pulmonary hypertension, mediating vascular remodelling, repair, and extracellular matrix deposition. It may also play a role in regulating vascular tone. More recently, it has been reported that adventitial fibroblasts can produce ET-1 after Ang II treatment. Additionally, emerging evidence suggests that the adventitia may be a potent source of vasoactive hormones such as growth factors and ET-1, which may regulate vascular structure and function via autocrine or paracrine signalling mechanisms. Despite these findings, many important questions regarding the role of the vascular adventitia remain unanswered, suggesting the need for further research to determine its exact function in health and disease.

scholarly journals Integrins: Moonlighting Proteins in Invadosome Formation

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 615 ◽  
Author(s):  
Rafael Peláez ◽  
Ana Pariente ◽  
Álvaro Pérez-Sala ◽  
Ignacio M. Larrayoz
Keyword(s):  
Extracellular Matrix ◽  
Plasma Membranes ◽  
General Term ◽  
Molecular Signaling ◽  
Ecm Remodeling ◽  
Cell Functions ◽  
And Function ◽  
Cell Matrix Interactions

Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation. These structures have an undoubted association with cancer invasion and metastasis because invadopodium formation in vivo is a key step for intra/extravasation of tumor cells. Invadopodia are closely related to other actin-rich structures known as podosomes, which are typical structures of normal cells necessary for different physiological processes during development and organogenesis. Invadopodia and podosomes are included in the general term ‘invadosomes,’ as they both appear as actin puncta on plasma membranes next to extracellular matrix metalloproteinases, although organization, regulation, and function are slightly different. Integrins are transmembrane proteins implicated in cell–cell and cell–matrix interactions and other important processes such as molecular signaling, mechano-transduction, and cell functions, e.g., adhesion, migration, or invasion. It is noteworthy that integrin expression is altered in many tumors, and other pathologies such as cardiovascular or immune dysfunctions. Over the last few years, growing evidence has suggested a role of integrins in the formation of invadopodia. However, their implication in invadopodia formation and adhesion to the ECM is still not well known. This review focuses on the role of integrins in invadopodium formation and provides a general overview of the involvement of these proteins in the mechanisms of metastasis, taking into account classic research through to the latest and most advanced work in the field.

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