scholarly journals Feedback regulation of BMP signaling by C. elegans cuticle collagens

2019 ◽  
Author(s):  
Uday Madaan ◽  
Lionel Faure ◽  
Albar Chowdhury ◽  
Shahrear Ahmed ◽  
Emma J. Ciccarelli ◽  
...  
Keyword(s):  
Body Size ◽  
Regulation Of Gene Expression ◽  
Feedback Regulation ◽  
Bmp Signaling ◽  
Physical Separation ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Cellular Responsiveness ◽  
Collagen Genes ◽  
Cuticle Collagens

AbstractCellular responsiveness to environmental cues, 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 allowing this responsiveness is the bone morphogenetic protein (BMP) signaling pathway. Due to their broad and potent functions, BMPs and their signaling pathways are highly regulated at multiple levels. In Caenorhabditis elegans, the BMP ligand DBL-1 is a major regulator of body size. We have previously shown that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We have now obtained evidence of feedback regulation of DBL-1/BMP by collagen genes. We analyzed four DBL-1-regulated collagen genes that affect body size. Here we show that inactivation of any one of these cuticle collagen genes reduces DBL-1/BMP signaling, as measured by a Smad activity reporter. Furthermore, we find that depletion of these collagens reduces GFP::DBL-1 fluorescence, and acts unexpectedly at the level of dbl-1 transcription. We therefore conclude that cuticle, a type of ECM, impinges on DBL-1/BMP expression and signaling. In contrast to other characterized examples, however, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact-independent, due to the physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel mechanism of regulation of BMP signaling, with broader implications for mechanical regulation of gene expression in general.

scholarly journals The C. elegans SMOC-1 protein acts cell non-autonomously to promote bone morphogenetic protein signaling

2018 ◽  
Author(s):  
Melisa S. DeGroot ◽  
Herong Shi ◽  
Alice Eastman ◽  
Alexandra N. McKillop ◽  
Jun Liu
Keyword(s):  
Body Size ◽  
Bone Morphogenetic Protein ◽  
Calcium Binding ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
Bmp Signaling ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Positive Modulator ◽  
Bmp Pathway

ABSTRACTBone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) null mutants have a small body size, while overexpression of smoc-1 led to a long body size and increased expression of the RAD-SMAD BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFβ-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell non-autonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1’s function in modulating BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans.ARTICLE SUMMARYBMP signaling is critical for development and homeostasis in metazoans, and is under tight regulation. We report the identification and characterization of a Secreted MOdular Calcium binding protein SMOC-1 as a positive modulator of BMP signaling in C. elegans. We established that SMOC-1 antagonizes the function of LON-2/glypican and acts through the DBL-1/BMP ligand to promote BMP signaling. We identified smoc-1-expressing cells, and demonstrated that SMOC-1 acts cell non-autonomously and in a positive feedback loop to regulate BMP signaling. We also provide evidence suggesting that the function of SMOC proteins in the BMP pathway is conserved from worms to humans.

scholarly journals BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes inCaenorhabditis elegans

Genetics ◽  
2018 ◽  
Vol 210 (4) ◽  
pp. 1355-1367 ◽  
Author(s):  
Uday Madaan ◽  
Edlira Yzeiraj ◽  
Michael Meade ◽  
James F. Clark ◽  
Christine A. Rushlow ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Body Size ◽  
Bmp Signaling ◽  
Collagen Genes

scholarly journals Feedback regulation of BMP signaling by Caenorhabditis elegans cuticle collagens

2020 ◽  
Vol 31 (8) ◽  
pp. 825-832 ◽  
Author(s):  
Uday Madaan ◽  
Lionel Faure ◽  
Albar Chowdhury ◽  
Shahrear Ahmed ◽  
Emma J. Ciccarelli ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Feedback Regulation ◽  
Bmp Signaling ◽  
Reciprocal Interactions ◽  
Growth Factor Beta ◽  
Cuticle Collagens

Transforming growth factor beta (TGF-β) and related signals can be regulated by the extracellular matrix (ECM). We identify a novel contact-independent regulation of DBL-1 TGF-β/BMP–related signaling by collagens in Caenorhabditis elegans. These collagens are transcriptional targets of the pathway, indicating reciprocal interactions between DBL-1 signaling and the ECM.

scholarly journals CD44 modulates Smad1 activation in the BMP-7 signaling pathway

2004 ◽  
Vol 166 (7) ◽  
pp. 1081-1091 ◽  
Author(s):  
Richard S. Peterson ◽  
Roma A. Andhare ◽  
Kathleen T. Rousche ◽  
Warren Knudson ◽  
Weihua Wang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Cytoplasmic Domain ◽  
Bmp Signaling ◽  
Cell Interactions ◽  
Full Length ◽  
Luciferase Reporter ◽  
Functional Link ◽  
Morphogenetic Protein ◽  
Smad Proteins ◽  
Cellular Responsiveness

Bone morphogenetic protein 7 (BMP-7) regulates cellular metabolism in embryonic and adult tissues. Signal transduction occurs through the activation of intracellular Smad proteins. In this paper, using a yeast two-hybrid screen, Smad1 was found to interact with the cytoplasmic domain of CD44, a receptor for the extracellular matrix macromolecule hyaluronan. Coimmunoprecipitation experiments confirmed the interaction of Smad1 with full-length CD44—interactions that did not occur when CD44 receptors truncated within the cytoplasmic domain were tested. Chondrocytes overexpressing a truncated CD44 on a background of endogenous full-length CD44 no longer exhibited Smad1 nuclear translocation upon BMP-7 stimulation. Further, pretreatment of chondrocytes with Streptomyces hyaluronidase to disrupt extracellular hyaluronan–cell interactions inhibited BMP-7–mediated Smad1 phosphorylation, nuclear translocation of Smad1 or Smad4, and SBE4–luciferase reporter activation. These results support a functional link between the BMP signaling cascade and CD44. Thus, changes in hyaluronan–cell interactions may serve as a means to modulate cellular responsiveness to BMP.

scholarly journals Mechanism of Interaction of BMP and Insulin Signaling in C. elegans Development and Homeostasis

2019 ◽  
Author(s):  
James F. Clark ◽  
Emma J. Ciccarelli ◽  
Gehan Ranepura ◽  
Muhammad S. Hasan ◽  
Alicia Meléndez ◽  
...  
Keyword(s):  
Bmp Signaling ◽  
Lipid Homeostasis ◽  
Signaling Crosstalk ◽  
C Elegans ◽  
Morphogenetic Protein ◽  
Autophagy Induction ◽  
Dauer Formation ◽  
And Function ◽  
Modes Of Interaction ◽  
Molecular Components

AbstractA small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not known. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is specifically regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing two additional IIS functions, dauer formation and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

scholarly journals Caenorhabditis elegans BMP Transcriptional Program Implicates Collagen Genes in Body Size Regulation

2017 ◽  
Author(s):  
Uday Madaan ◽  
Edlira Yzeiraj ◽  
Michael Meade ◽  
Christine A. Rushlow ◽  
Cathy Savage-Dunn
Keyword(s):  
Body Size ◽  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
Transcriptional Network ◽  
Bmp Signaling ◽  
Functional Impairments ◽  
Size Regulation ◽  
Downstream Effectors ◽  
Bmp Pathway ◽  
Collagen Genes

AbstractBody size is a tightly regulated phenotype in metazoans that is dependent on both intrinsic and extrinsic factors. While signaling pathways such as insulin, Hippo, and myostatin are known to control organ and body size, the downstream effectors that mediate their effects are still poorly understood. In the nematode C. elegans, a Bone Morphogenetic Protein (BMP)-related signaling pathway is the major regulator of growth and body size. DBL-1, the BMP-related ligand, is secreted by neurons and body wall muscle, and acts as a dose-dependent regulator of body size. We investigated the transcriptional network through which the DBL-1/BMP pathway regulates body size and identified cuticle collagen genes as major effectors of growth control. Here we demonstrate that cuticle collagen genes can act as positive regulators (col-41), dose-sensitive regulators (rol-6), and negative regulators (col-141, col-142) of body size. Moreover, we show requirement of DBL-1/BMP signaling for stage-specific expression of cuticle collagen genes. We used chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq) and electrophoretic mobility shift assays to show that the Smad signal transducers directly associate with conserved Smad binding elements in regulatory regions of col-141 and col-142, but not of col-41. Hence, cuticle collagen genes are directly and indirectly regulated via the DBL-1/BMP pathway. These results provide the first direct regulatory link between this conserved signaling pathway and the collagen genes that act as its downstream effectors in body size regulation. 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.Author SummaryBody size in humans and other animals is determined by the combined influence of genetic and environmental factors. Failure to regulate growth and body size appropriately can lead to a variety of functional impairments and reduced fitness. Progress has been made in identifying genetic determinants of body size, but these have not often been connected into functional pathways. In the nematode model Caenorhabditis elegans, single gene mutations in the BMP signaling pathway have profound effects on body size. Here we have elucidated the BMP transcriptional network and identified cuticle collagen genes as downstream effectors of body size regulation through the BMP pathway. Collagens play diverse roles in biology; mutations are often associated with rare heritable diseases such as osteogenesis imperfecta and Ehlers-Danlos syndrome. Our work thus connects a conserved signaling pathway with its critical downstream effectors, advancing insight into how body size is specified.

scholarly journals Analysis of mutations in the sqt-1 and rol-6 collagen genes of Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 135 (4) ◽  
pp. 1035-1045 ◽  
Author(s):  
J M Kramer ◽  
J J Johnson
Keyword(s):  
Caenorhabditis Elegans ◽  
Nonsense Mutation ◽  
Cysteine Residue ◽  
Nonsense Mutations ◽  
C Elegans ◽  
Conserved Sequence ◽  
Amino Terminal ◽  
Carboxy Terminal ◽  
Collagen Genes ◽  
Cuticle Collagens

Abstract Different mutations in the sqt-1 and rol-6 collagen genes of Caenorhabditis elegans can cause diverse changes in body morphology and display different genetic attributes. We have determined the nucleotide alterations in 15 mutant alleles of these genes. Three mutations in sqt-1 and one in rol-6 that cause dominant right-handed helical twisting (RRol) of animals are arginine to cysteine replacements. These mutations are all within a short conserved sequence, on the amino terminal side of the Gly-X-Y repeats, that is found in all C. elegans cuticle collagens. A recessive RRol mutation of rol-6 is a replacement of one of the same conserved arginines by histidine. In contrast, three sqt-1 mutations that cause recessive left-handed helical twisting (LRol) are replacements of a conserved carboxy-terminal cysteine residue with either tyrosine or serine. These results suggest that disulfide bonding is important in collagen organization and that a deficit or surplus of disulfides may cause cuticle alterations of opposite handedness. In contrast to other collagens, glycine replacement mutations in the Gly-X-Y repeats of sqt-1 cause very mild phenotypes. Nonsense mutations of both sqt-1 and rol-6 cause nearly, but not totally, wild-type phenotypes. A nonsense mutation in sqt-1 suppresses the phenotype of rol-6 RRol mutations, suggesting that rol-6 collagen function is dependent on the presence of sqt-1 collagen. Mutations of sqt-1 are not suppressed by a rol-6 nonsense mutation, however, indicating that sqt-1 collagen can function independently of rol-6.

scholarly journals Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

2021 ◽  
Vol 7 (7) ◽  
pp. eabf1798
Author(s):  
A. Murashima-Suginami ◽  
H. Kiso ◽  
Y. Tokita ◽  
E. Mihara ◽  
Y. Nambu ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Tooth Agenesis ◽  
Tooth Regeneration ◽  
Missing Teeth ◽  
Morphogenetic Protein ◽  
Genetic Abnormalities ◽  
Direct Binding ◽  
Tooth Germs ◽  
Lipoprotein Receptor Related Protein

Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

scholarly journals GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

2020 ◽  
Vol 117 (9) ◽  
pp. 4910-4920 ◽  
Author(s):  
Joonho Suh ◽  
Na-Kyung Kim ◽  
Seung-Hoon Lee ◽  
Je-Hyun Eom ◽  
Youngkyun Lee ◽  
...  
Keyword(s):  
Bone Mass ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Biochemical Properties ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

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